Descriptor: "MESH : Mice, Transgenic" - Searchworks@Jio Institute Digital Library Search Results

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45 results on '"MESH : Mice, Transgenic"'

1. Comparative Study of Injury Models for Studying Muscle Regeneration in Mice

Author: Shahragim Tajbakhsh, Cédric Thépenier, David Briand, Aurélie Guguin, Aurore Besnard, Mathilde Latil, Pierre Rocheteau, Grégory Jouvion, Jean-Marc Cavaillon, Quentin Pascal, Fabrice Chrétien, David Hardy, Barbara Gayraud-Morel, Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Université Paris Descartes - Paris 5 ( UPD5 ), Institut de Recherche Biomédicale des Armées ( IRBA ), Plateforme de Cytométrie en Flux, GHU A. Chenevier - Henri Mondor ( Inserm U955, équipe 16 ), Cellules Souches et Développement, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Cytokines et Inflammation, This work was financially supported by AFM-vaincre les myopathies ([http://www.afm-telethon.fr/] Role: design, data collection and analysis), Fondation ³Les gueules cassées², Institut Pasteur and Région Ile de France. his work wasalso supported by the agence-nationale-recherche ([http://www.agence-nationale-recherche.fr/], Role:design, data collection and analysis). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of themanuscript, Institut Pasteur [Paris] (IP), Université Paris Descartes - Paris 5 (UPD5), Institut de Recherche Biomédicale des Armées (IRBA), GHU A. Chenevier - Henri Mondor (Inserm U955, équipe 16), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), BENEDIC, Bénédicte, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: Pathology, MESH : Cytokines, Barium Compounds, MESH: Barium Compounds, Pathology and Laboratory Medicine, Muscle Development, MESH : Green Fluorescent Proteins, Mice, Animal Cells, Fibrosis, Freezing, MESH : Chlorides, MESH: Animals, lcsh:Science, MESH : Muscle, Skeletal, Immune Response, Musculoskeletal System, MESH : Macrophages, Innate Immune System, MESH: Cytokines, MESH : Neovascularization, Physiologic, Stem Cells, MESH: Satellite Cells, Skeletal Muscle, MESH : Mice, Transgenic, 3. Good health, [SDV] Life Sciences [q-bio], Neurology, MESH: Cold Injury, Cytokines, Cellular Types, Muscle Regeneration, medicine.medical_specialty, Satellite Cells, Skeletal Muscle, Immune Cells, Immunology, MESH : Muscle Development, Neovascularization, Physiologic, MESH : Myoblasts, Necrosis, 03 medical and health sciences, Signs and Symptoms, Cardiotoxin, MESH: Green Fluorescent Proteins, Regeneration, MESH: Chlorides, Cold Injury, MESH: Elapid Venoms, MESH : Cobra Cardiotoxin Proteins, Blood Cells, MESH: Vascular Endothelial Growth Factor Receptor-2, [ SDV ] Life Sciences [q-bio], [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Macrophages, Regeneration (biology), lcsh:R, Biology and Life Sciences, Molecular Development, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, MESH : Necrosis, Mice, Inbred C57BL, Biological Tissue, 030104 developmental biology, Skeletal Muscles, lcsh:Q, Organism Development, Developmental Biology, MESH: Freezing, 0301 basic medicine, Physiology, [SDV]Life Sciences [q-bio], Cobra Cardiotoxin Proteins, Poison control, lcsh:Medicine, Myoblasts, White Blood Cells, Immune Physiology, Neurobiology of Disease and Regeneration, Morphogenesis, Medicine and Health Sciences, Myocyte, MESH: Muscle, Skeletal, Multidisciplinary, Muscles, MESH: Regeneration, MESH: Cobra Cardiotoxin Proteins, medicine.anatomical_structure, MESH: Models, Animal, Models, Animal, MESH: Fibrosis, MESH : Barium Compounds, MESH : Stem Cells, MESH : Fibrosis, MESH: Muscle Development, Basal lamina, Anatomy, Stem cell, medicine.symptom, MESH: Neovascularization, Physiologic, Research Article, MESH : Cold Injury, Histology, MESH: Mice, Transgenic, MESH : Elapid Venoms, Green Fluorescent Proteins, MESH : Vascular Endothelial Growth Factor Receptor-2, Muscle Tissue, Mice, Transgenic, MESH : Regeneration, MESH: Stem Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH : Mice, Inbred C57BL, Biology, Andrology, Chlorides, MESH: Mice, Inbred C57BL, MESH : Satellite Cells, Skeletal Muscle, MESH : Mice, medicine, Animals, MESH: Myoblasts, Muscle, Skeletal, MESH: Mice, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Inflammation, Elapid Venoms, MESH: Necrosis, MESH: Macrophages, Cell Biology, MESH : Models, Animal, MESH : Freezing, Immune System, MESH : Animals
Abstract: International audience; A longstanding goal in regenerative medicine is to reconstitute functional tissues or organs after injury or disease. Attention has focused on the identification and relative contribution of tissue specific stem cells to the regeneration process. Relatively little is known about how the physiological process is regulated by other tissue constituents. Numerous injury models are used to investigate tissue regeneration, however, these models are often poorly understood. Specifically, for skeletal muscle regeneration several models are reported in the literature, yet the relative impact on muscle physiology and the distinct cells types have not been extensively characterised. We have used transgenic Tg:Pax7nGFP and Flk1GFP/+ mouse models to respectively count the number of muscle stem (satellite) cells (SC) and number/shape of vessels by confocal microscopy. We performed histological and immunostainings to assess the differences in the key regeneration steps. Infiltration of immune cells, chemokines and cytokines production was assessed in vivo by Luminex®.We compared the 4 most commonly used injury models i.e. freeze injury (FI), barium chloride (BaCl2), notexin (NTX) and cardiotoxin (CTX). The FI was the most damaging. In this model, up to 96% of the SCs are destroyed with their surrounding environment (basal lamina and vasculature) leaving a "dead zone" devoid of viable cells. The regeneration process itself is fulfilled in all 4 models with virtually no fibrosis 28 days post-injury, except in the FI model. Inflammatory cells return to basal levels in the CTX, BaCl2 but still significantly high 1-month post-injury in the FI and NTX models. Interestingly the number of SC returned to normal only in the FI, 1-month post-injury, with SCs that are still cycling up to 3-months after the induction of the injury in the other models.We compared the 4 most commonly used injury models i.e. freeze injury (FI), barium chloride (BaCl2), notexin (NTX) and cardiotoxin (CTX). The FI was the most damaging. In this model, up to 96% of the SCs are destroyed with their surrounding environment (basal lamina and vasculature) leaving a "dead zone" devoid of viable cells. The regeneration process itself is fulfilled in all 4 models with virtually no fibrosis 28 days post-injury, except in the FI model. Inflammatory cells return to basal levels in the CTX, BaCl2 but still significantly high 1-month post-injury in the FI and NTX models. Interestingly the number of SC returned to normal only in the FI, 1-month post-injury, with SCs that are still cycling up to 3-months after the induction of the injury in the other models.We compared the 4 most commonly used injury models i.e. freeze injury (FI), barium chloride (BaCl2), notexin (NTX) and cardiotoxin (CTX). The FI was the most damaging. In this model, up to 96% of the SCs are destroyed with their surrounding environment (basal lamina and vasculature) leaving a "dead zone" devoid of viable cells. The regeneration process itself is fulfilled in all 4 models with virtually no fibrosis 28 days post-injury, except in the FI model. Inflammatory cells return to basal levels in the CTX, BaCl2 but still significantly high 1-month post-injury in the FI and NTX models. Interestingly the number of SC returned to normal only in the FI, 1-month post-injury, with SCs that are still cycling up to 3-months after the induction of the injury in the other models.
Published: 2016
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2. Food Intake Adaptation to Dietary Fat Involves PSA-Dependent Rewiring of the Arcuate Melanocortin System in Mice

Author: Christophe Guissard, Cecile Hryhorczuk, Caroline Rigault, André Colom, Emmanuelle Nédélec, Luc Pénicaud, Anne Lorsignol, Claude Knauf, Philippe Valet, Alexandra Gouazé, Xavier Fioramonti, Alexandre Benani, Rita Gerardy-Schahn, Alice Krezymon, Thibaut Duparc, Aleth Lemoine, Xavier Brenachot, Jean Gascuel, Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Hôpital de Rangueil-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherches sur la Cognition Animale [Toulouse] ( CRCA ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches sur la Cognition Animale (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), STROMALab, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), CNRS, Institut National de la Recherche Agronomique, Agence Nationale de la Recherche [ANR-05-PNRA-004], Burgundy county [FABER-2009-9201-AAO036S00635], Association Francaise d'Etudes et de Recherches sur l'Obesite, and Institut B. Delessert
Subjects: Male, MESH: Signal Transduction, Pro-Opiomelanocortin, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, SYNAPTIC INPUT ORGANIZATION, MESH: Energy Intake, Weight Gain, MESH: Mice, Knockout, Mice, 0302 clinical medicine, MESH : Sialic Acids, NPY/AGRP NEURONS, MESH: Pro-Opiomelanocortin, MESH: Animals, MESH : Neuronal Plasticity, MESH: Neuronal Plasticity, PLASTICITY, MESH : Pro-Opiomelanocortin, MESH : Adaptation, Physiological, Mice, Knockout, FEEDING CIRCUITS, MESH : Organ Culture Techniques, INSULIN-RESISTANCE, 0303 health sciences, Neuronal Plasticity, POLYSIALIC ACID, General Neuroscience, Leptin, MESH: Energy Metabolism, digestive, oral, and skin physiology, INDUCED OBESITY, MESH : Sialyltransferases, MESH : Weight Gain, Articles, Adaptation, Physiological, MESH : Mice, Transgenic, BODY-WEIGHT, MESH: Dietary Fats, Hypothalamus, CELL-ADHESION MOLECULE, MESH: Weight Gain, Ghrelin, ENERGY-BALANCE, Melanocortin, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, medicine.medical_specialty, MESH: Mice, Transgenic, MESH : Male, MESH: Sialyltransferases, MESH: Arcuate Nucleus, Mice, Transgenic, MESH : Mice, Inbred C57BL, Biology, MESH : Arcuate Nucleus, MESH: Sialic Acids, 03 medical and health sciences, Organ Culture Techniques, Insulin resistance, MESH: Mice, Inbred C57BL, Arcuate nucleus, Internal medicine, MESH : Mice, medicine, Animals, MESH: Mice, 030304 developmental biology, MESH : Signal Transduction, Arcuate Nucleus of Hypothalamus, MESH : Energy Intake, medicine.disease, Dietary Fats, MESH: Adaptation, Physiological, Sialyltransferases, MESH: Organ Culture Techniques, MESH: Male, Mice, Inbred C57BL, MESH : Energy Metabolism, Endocrinology, MESH: Nerve Net, Sialic Acids, MESH : Nerve Net, MESH : Mice, Knockout, MESH : Animals, Nerve Net, Energy Intake, Energy Metabolism, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH : Dietary Fats, 030217 neurology & neurosurgery, Homeostasis, Hormone
Abstract: International audience; Hormones such as leptin and ghrelin can rapidly rewire hypothalamic feeding circuits when injected into rodent brains. These experimental manipulations suggest that the hypothalamus might reorganize continually in adulthood to integrate the metabolic status of the whole body. In this study, we examined whether hypothalamic plasticity occurs in naive animals according to their nutritional conditions. For this purpose, we fed mice with a short-term high-fat diet (HFD) and assessed brain remodeling through its molecular and functional signature. We found that HFD for 3 d rewired the hypothalamic arcuate nucleus, increasing the anorexigenic tone due to activated pro-opiomelanocortin (POMC) neurons. We identified the polysialic acid molecule (PSA) as a mediator of the diet-induced rewiring of arcuate POMC. Moreover, local pharmacological inhibition and genetic disruption of the PSA signaling limits the behavioral and metabolic adaptation to HFD, as treated mice failed to normalize energy intake and showed increased body weight gain after the HFD challenge. Altogether, these findings reveal the existence of physiological hypothalamic rewiring involved in the homeostatic response to dietary fat. Furthermore, defects in the hypothalamic plasticity-driven adaptive response to HFD are obesogenic and could be involved in the development of metabolic diseases.
Published: 2012
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3. Bone resorption control of tooth eruption and root morphogenesis: Involvement of the receptor activator of NF-κB (RANK)

Author: Frédéric Lézot, Yohann Simon, Yong-Wong Choi, Estelle Hess, Ariane Berdal, Claudine Blin-Wakkach, Jaime Jacques, Christopher G. Mueller, Beatriz Castaneda, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculty of Odontology, Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Régulations des réactions immunitaires et inflammatoires, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Français pour la Recherche Odontologique (IFRO) & University of Antioquia, UdeA, Colombia, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Immunologie et chimie thérapeutiques ( ICT ), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique ( CNRS ), University of Pennsylvania School of Medicine, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -IFR50-Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of Pennsylvania-University of Pennsylvania, and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Osteolysis, Physiology, Clinical Biochemistry, Tooth eruption, MESH : Promoter Regions, Genetic, Tooth Eruption, Mice, 0302 clinical medicine, MESH: Tooth Root, MESH: Animals, Tooth Root, Promoter Regions, Genetic, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 0303 health sciences, MESH : Gene Expression Regulation, Receptor Activator of Nuclear Factor-kappa B, Anatomy, MESH: Gene Expression Regulation, MESH : Mice, Transgenic, MESH : Bone Remodeling, MESH: Tooth Eruption, medicine.anatomical_structure, MESH: ATP-Binding Cassette Transporters, Bone Remodeling, Genetically modified mouse, medicine.medical_specialty, MESH: Mice, Transgenic, Mice, Transgenic, Biology, Bone resorption, 03 medical and health sciences, Osteoclast, MESH: Bone Remodeling, Internal medicine, MESH : Mice, MESH: Promoter Regions, Genetic, medicine, Animals, MESH : ATP-Binding Cassette Transporters, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, MESH: Mice, Dental alveolus, MESH : Receptor Activator of Nuclear Factor-kappa B, 030304 developmental biology, Activator (genetics), MESH : Tooth Eruption, MESH : Tooth Root, Osteopetrosis, 030206 dentistry, Cell Biology, medicine.disease, Endocrinology, Gene Expression Regulation, MESH: Receptor Activator of Nuclear Factor-kappa B, ATP-Binding Cassette Transporters, MESH : Animals
Abstract: International audience; Activation of the receptor activator of NF-κB (RANK) is a crucial step in osteoclastogenesis. Loss- and gain-of-function mutations in the Rank gene cause, respectively, osteopetrosis and several forms of extensive osteolysis. Tooth and alveolar bone alterations are associated with these pathologies but remain to be better characterized. The aim of the present study was to establish the tooth and alveolar bone phenotype of a transgenic mouse model of RANK over-expression in osteoclast precursors. Early tooth eruption and accelerated tooth root elongation were observed subsequent to an increase in osteoclast numbers surrounding the tooth. The final root length appeared not to be affected by RANK over-expression, but a significant reduction in root diameter occurred in both control and root-morphogenesis-defective Msx2 null mutant mice. These results indicate that root length is independent of the surrounding bone resorption activity. In contrast, root diameter is sensitive to the activity of alveolar bone osteoclasts. These data suggest that early eruption and thin root are phenotypic features that could be associated with extensive osteolytic pathologies.
Published: 2010
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4. MuSK frizzled-like domain is critical for mammalian neuromuscular junction formation and maintenance

Author: Julien Messéant, Marin Manuel, Daniel Zytnicki, Alexandre Dobbertin, Laurent Schaeffer, Claire Legay, Alain Schmitt, Perrine Delers, Emmanuelle Girard, Francesca Mangione, Laure Strochlic, Dominique Le Denmat, Jordi Molgó, Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologies, Imagerie et Biothérapies oro-faciales (EA 2496), Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Neurophysique et physiologie du système moteur (NPSM), Biologie des Jonctions Neuromusculaires Normales et Pathologiques (U686), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut des Neurosciences Paris-Saclay (NeuroPSI), Association Francaise contre les Myopathies (14960, 18046), Centre National de la Recherche Scientifique, Paris Descartes University, Institut National de la Sante et de la Recherche Medicale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de neurophysique, physiologie, pathologie ( UMR 8119 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Pathologies, Imagerie et Biothérapies oro-faciales ( EA 2496 ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Neurosciences de Paris-Saclay ( Neuro-PSI ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Neurophysique et physiologie du système moteur ( NPSM ), and Biologie des Jonctions Neuromusculaires Normales et Pathologiques ( U686 )
Subjects: Male, MESH: Fatigue, Frizzled, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH : Muscle Weakness, Synaptogenesis, MESH: Animals, Newborn, Synapse, Mice, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, Receptors, Cholinergic, MESH : Female, MESH: Animals, Fatigue, MuSK, Motor Neurons, 0303 health sciences, Muscle Weakness, synaptogenesis, Hand Strength, neuromuscular junction, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH : Animals, Newborn, General Neuroscience, Intracellular Signaling Peptides and Proteins, Wnt signaling pathway, MESH: Muscle Weakness, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH: Lithium Chloride, Articles, Congenital myasthenic syndrome, MESH : Mice, Transgenic, MESH : Fatigue, medicine.anatomical_structure, MESH: Hand Strength, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Acetylcholinesterase, Female, MESH: Receptor Protein-Tyrosine Kinases, MESH : Mutation, medicine.symptom, MESH : Lithium Chloride, MESH : Hand Strength, MESH: Motor Neurons, MESH: Myasthenic Syndromes, Congenital, animal structures, MESH: Mutation, MESH : Motor Neurons, MESH: Mice, Transgenic, MESH : Male, Primary Cell Culture, MESH: Glycoproteins, Mice, Transgenic, Biology, MESH : Myasthenic Syndromes, Congenital, Neuromuscular junction, MESH : Acetylcholinesterase, [ SDV.NEU.PC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Primary Cell Culture, 03 medical and health sciences, Wnt, MESH : Mice, medicine, Animals, MESH : Primary Cell Culture, MESH: Mice, lithium chloride, Glycoproteins, 030304 developmental biology, Acetylcholine receptor, Myasthenic Syndromes, Congenital, MESH: Receptors, Cholinergic, Receptor Protein-Tyrosine Kinases, Muscle weakness, MESH : Receptor Protein-Tyrosine Kinases, MESH: Acetylcholinesterase, MESH : Receptors, Cholinergic, medicine.disease, MESH : Glycoproteins, MESH: Male, MESH : Pregnancy, Animals, Newborn, nervous system, congenital myasthenic syndrome, Mutation, MESH : Neuromuscular Junction, MESH : Animals, MESH: Neuromuscular Junction, Neuroscience, MESH: Female, 030217 neurology & neurosurgery
Abstract: The muscle-specific kinase MuSK is one of the key molecules orchestrating neuromuscular junction (NMJ) formation. MuSK interacts with the Wnt morphogens, through its Frizzled-like domain (cysteine-rich domain [CRD]). Dysfunction of MuSK CRD in patients has been recently associated with the onset of myasthenia, common neuromuscular disorders mainly characterized by fatigable muscle weakness. However, the physiological role of Wnt-MuSK interaction in NMJ formation and function remains to be elucidated. Here, we demonstrate that the CRD deletion of MuSK in mice caused profound defects of both muscle prepatterning, the first step of NMJ formation, and synapse differentiation associated with a drastic deficit in AChR clusters and excessive growth of motor axons that bypass AChR clusters. Moreover, adultMuSKΔCRDmice developed signs of congenital myasthenia, including severe NMJs dismantlement, muscle weakness, and fatigability. We also report, for the first time, the beneficial effects of lithium chloride, a reversible inhibitor of the glycogen synthase kinase-3, that rescued NMJ defects inMuSKΔCRDmice and therefore constitutes a novel therapeutic reagent for the treatment of neuromuscular disorders linked to Wnt-MuSK signaling pathway deficiency. Together, our data reveal that MuSK CRD is critical for NMJ formation and plays an unsuspected role in NMJ maintenance in adulthood.
Published: 2015
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5. Widespread lipoplex-mediated gene transfer to vascular endothelial cells and hemangioblasts in the vertebrate embryo

Author: Daniel Scherman, Daisuke Sugiyama, Rodolphe Gautier, Karine Bollerot, Samuel Tozer, Thierry Jaffredo, Virginie Escriou, Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Laboratoire de Biologie du Développement ( LBD ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Unité de Pharmacologie Chimique et Génétique ( UPCG - UMR_S 640/UMR 8151 ), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Génétique, Pharmacologie Chimique Et
Subjects: Vascular Endothelial Growth Factor A, MESH : Va, MESH : Animals, Genetically Modified, MESH: Va, MESH : RNA, Small Interfering, MESH: Hematopoietic Stem Cells, Animals, Genetically Modified, Mice, 0302 clinical medicine, MESH: Genetic Vectors, RNA interference, MESH: RNA, Small Interfering, MESH: Animals, MESH: Endothelial Cells, RNA, Small Interfering, 0303 health sciences, MESH : Neovascularization, Physiologic, Gene Transfer Techniques, Embryo, Transfection, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH : Mice, Transgenic, MESH : Genetic Vectors, Cell biology, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Haematopoiesis, medicine.anatomical_structure, Hemangioblast, MESH: Endothelium, Vascular, Stem cell, Functional genomics, MESH: Neovascularization, Physiologic, Endothelium, MESH: Mice, Transgenic, Genetic Vectors, Neovascularization, Physiologic, Mice, Transgenic, MESH: Gene Transfer Techniques, Biology, MESH: Animals, Genetically Modified, 03 medical and health sciences, MESH : Mice, medicine, Animals, MESH : Gene Transfer Techniques, MESH: Mice, 030304 developmental biology, MESH : Embryo, MESH : Endothelial Cells, MESH : Hematopoietic Stem Cells, MESH: Embryo, Endothelial Cells, Embryo, Mammalian, Hematopoietic Stem Cells, Molecular biology, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences, MESH : Endothelium, Vascular, MESH : Liposomes, Liposomes, MESH: Liposomes, Endothelium, Vascular, MESH : Animals, 030217 neurology & neurosurgery, Developmental Biology
Abstract: We report here a method that allows fast, efficient, and low-cost screening for gene function in the vascular system of the vertebrate embryo. Through intracardiac delivery of nucleic acids optimally compacted by a specific cationic lipid, we are able to induce in vivo endothelial cell-specific gain-of-function during development of the vascular network in the chick embryo. When the nucleic acids are delivered during the period of intraembryonic hematopoiesis, aortic hemangioblasts, the forerunners of the hematopoietic stem cells known to derive from the aortic endothelium, are also labeled. Similarly, we show that siRNA could be used to induce loss-of-function in vascular endothelial cells. This gene transfer technique was also applied to the mouse embryo with a high efficiency. The present method allows large-scale analysis and may represent a new and versatile tool for functional genomics.
Published: 2006
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6. Invariant NKT cells regulate the CD8 T cell response during Theiler's virus infection

Author: Roland S. Liblau, Maria Leite-de-Moraes, Magali Mas, Lucie Beaudoin, Jean-François Bureau, Lennart T. Mars, Agnès Lehuen, Jan Bauer, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department Neuroimmunology, Medizinische Universität Wien = Medical University of Vienna-Center for Brain Research, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), the French MS society (ARSEP), the Midi-Pyrénées Region, and the Agence National de la Recherche (ANR-06-MIME), Medizinische Universität Wien = Medical University of Vienna-Center for Brain Research [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Bos, Mireille, Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Medical University of Vienna-Center for Brain Research, Cytokines, hématopoïèse et réponse immune ( CHRI ), Génétique fonctionnelle des Maladies infectieuses, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Central Nervous System, MESH: Inflammation, Mouse, MESH: Spleen, Encephalomyelitis, viruses, Neuroimmunology, Priming (immunology), MESH : Poliomyelitis, MESH: Lymph Nodes, MESH: T-Lymphocyte Subsets, Immune Privilege, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Epitope, Epitopes, Mice, T-Lymphocyte Subsets, Cytotoxic T cell, MESH: Animals, Immune Response, MESH : Lymph Nodes, Multidisciplinary, T Cells, MESH : Central Nervous System, virus diseases, Animal Models, MESH : CD8-Positive T-Lymphocytes, Natural killer T cell, MESH: CD8-Positive T-Lymphocytes, MESH : Mice, Transgenic, Innate Immunity, 3. Good health, medicine.anatomical_structure, MESH: Encephalomyelitis, Medicine, Research Article, MESH : Spleen, MESH: Epitopes, MESH: Mice, Transgenic, Immune Cells, T cell, Science, Immunology, Mice, Transgenic, MESH : Mice, Inbred C57BL, MESH : Epitopes, Biology, Model Organisms, Immune system, Theilovirus, MESH: Mice, Inbred C57BL, MESH : Mice, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, MESH: Central Nervous System, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Lymphocyte Activation, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Immunity to Infections, MESH: Mice, MESH : Lymphocyte Activation, MESH : Encephalomyelitis, Inflammation, MESH : Inflammation, T-cell receptor, Immunity, Immunoregulation, MESH : Theilovirus, Immunologic Subspecialties, medicine.disease, MESH : Natural Killer T-Cells, Virology, MESH : T-Lymphocyte Subsets, Mice, Inbred C57BL, MESH: Theilovirus, MESH: Natural Killer T-Cells, MESH: Poliomyelitis, Natural Killer T-Cells, Clinical Immunology, MESH : Animals, Lymph Nodes, Spleen, Poliomyelitis
Abstract: International audience; Invariant NKT cells are innate lymphocytes with a broad tissue distribution. Here we demonstrate that iNKT cells reside in the central nervous system (CNS) in the absence of inflammation. Their presence in the CNS dramatically augments following inoculation of C57Bl/6 mice with the neurotropic Theiler's murine encephalomyelitis virus (TMEV). At the peak of inflammation the cellular infiltrate comprises 45,000 iNKT cells for 1250 CD8 T cells specific for the immunodominant TMEV epitope. To study the interaction between these two T cell subsets, we infected both iNKT cell deficient Jα18(-/-) mice and iNKT cell enriched Vα14 transgenic mice with TMEV. The CD8 T cell response readily cleared TMEV infection in the iNKT cell deficient mice. However, in the iNKT cell enriched mice TMEV infection persisted and was associated with significant mortality. This was caused by the inhibition of the CD8 T cell response in the cervical lymph nodes and spleen after T cell priming. Taken together we demonstrate that iNKT cells reside in the CNS in the absence of inflammation and that their enrichment is associated with the inhibition of the anti-viral CD8 T cell response and an augmented mortality during acute encephalomyelitis.
Published: 2014
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7. CLIPR-59: a protein essential for neuromuscular junction stability during mouse late embryonic development

Author: Véronique Bernard, Stéphanie Backer, Evelyne Bloch-Gallego, Nathalie Chaverot, Ariane Dimitrov, Jordi Molgó, Franck Perez, Nicolas Offner, Aurélie Couesnon, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Neurobiologie et Développement (N&eD), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CNRS, Laboratoire de Neurobiologie et Développement, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Compartimentation et dynamique cellulaires ( CDC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Neurobiologie et Développement ( N&eD ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Neurobiologie Alfred Fessard ( INAF ), and Centre National de la Recherche Scientifique ( CNRS )
Subjects: Mutant, MESH: Spinal Cord, Mice, MESH : Embryonic Development, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, MESH: Gestational Age, MESH : Embryo, Mammalian, Homeostasis, MESH: Embryonic Development, MESH : Female, MESH: Animals, Axon, Respiratory system, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, 0303 health sciences, Brain, Anatomy, MESH : Mice, Transgenic, Cell biology, medicine.anatomical_structure, Spinal Cord, MESH: Homeostasis, MESH : Homeostasis, Knockout mouse, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microtubule-Associated Proteins, MESH: Cells, Cultured, MESH: Mice, Transgenic, Neuromuscular Junction, Embryonic Development, Gestational Age, Mice, Transgenic, MESH : Mice, Inbred C57BL, Biology, Contractility, 03 medical and health sciences, MESH: Brain, MESH: Mice, Inbred C57BL, MESH : Cells, Cultured, MESH : Mice, medicine, Animals, Molecular Biology, MESH: Mice, 030304 developmental biology, Embryogenesis, MESH: Embryo, Mammalian, MESH : Spinal Cord, Embryo, Mammalian, Embryonic stem cell, Mice, Inbred C57BL, MESH : Pregnancy, MESH: Microtubule-Associated Proteins, MESH : Brain, nervous system, MESH : Microtubule-Associated Proteins, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Neuromuscular Junction, Axon guidance, MESH : Animals, MESH: Neuromuscular Junction, MESH: Female, 030217 neurology & neurosurgery, MESH : Gestational Age, Developmental Biology
Abstract: International audience; CLIPR-59 is a new member of the cytoplasmic linker proteins (CLIP) family mainly localized to the trans-Golgi network. We show here that Clipr-59 expression in mice is restricted to specific pools of neurons, in particular motoneurons (MNs), and progressively increases from embryonic day 12.5 (E12.5) until the first postnatal days. We generated a Clipr-59 knockout mouse model that presents perinatal lethality due to respiratory defects. Physiological experiments revealed that this altered innervation prevents the normal nerve-elicited contraction of the mutant diaphragm that is reduced both in amplitude and fatigue-resistance at E18.5, despite unaffected functional muscular contractility. Innervation of the mutant diaphragm is not altered until E15.5, but is then partially lost in the most distal parts of the muscle. Ultrastructural observations of neuromuscular junctions (NMJs) in the distal region of the diaphragm reveal a normal organization, but a lower density of nerve terminals capped by terminal Schwann cells in E18.5 mutant when compared with control embryos. Similar defects in NMJ stability, with a hierarchy of severity along the caudo-rostral axis, are also observed in other muscles innervated by facial and spinal MNs in Clipr-59 mutant mice. Clipr-59 deficiency therefore affects axon maintenance but not axon guidance toward muscle targets. Thus, CLIPR-59 is involved in the stabilization of specific motor axons at the NMJ during mouse late embryogenesis and its role is crucial for mouse perinatal development.
Published: 2013
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8. Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy

Author: Anastasia R. Goloudina, Elena Y. Kochetkova, Marc Bardou, Arlette Hammann, Oleg N. Demidov, Sarah Richaud, Carmen Garrido, Olga A. Fedorova, Nickolai A. Barlev, Burhan Uyanik, V Clausse, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institute of Cytology of the Russian Academy of Science (St. Petersburg), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Fondation ARC, laboratoire d'excellence ARC, La Ligue Contre le Cancer CCIR-GE (14-15-00636 ), fondation scientifique russe, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), and UNICANCER
Subjects: Wip1, Apoptosis, Cell Cycle Proteins, Pharmacology, MESH: G2 Phase Cell Cycle Checkpoints, Histones, MESH : Phosphorylation, Mice, MESH : Cell Cycle Proteins, MESH: Animals, MESH: Tumor Suppressor Protein p53, MESH: Histones, Kinase, Tp53 mutations, MESH : Mice, Transgenic, 3. Good health, Protein Phosphatase 2C, Survival Rate, MESH : Antineoplastic Agents, H2ax phosphorylation, P53 activation, MESH: Protein Phosphatase 2C, RNA Interference, MESH : Colorectal Neoplasms, MESH : Carrier Proteins, Histone H2ax, MESH: Mitochondria, Immunology, Human fibroblasts, MESH: Carrier Proteins, Antineoplastic Agents, MESH: Protein-Tyrosine Kinases, MESH: Protein-Serine-Threonine Kinases, MESH : Cisplatin, 03 medical and health sciences, MESH: Cell Cycle Proteins, Genotoxic stress, MESH : Protein-Tyrosine Kinases, Humans, MESH : Histones, Anticancer Therapy, MESH: DNA Damage, Cisplatin, MESH: Humans, MESH: Phosphorylation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH : Humans, MESH : Nuclear Proteins, 030104 developmental biology, Cancer cell, MESH: Antineoplastic Agents, Carrier Proteins, MESH: Nuclear Proteins, MESH : Apoptosis, Dna-damage response, 0301 basic medicine, Cancer Research, MESH: Caspase 3, MESH : Caspase 3, Phosphorylation, Cytotoxicity, MESH : DNA Damage, Sensitization, medicine.diagnostic_test, Caspase 3, Nuclear Proteins, Protein-Tyrosine Kinases, MESH : Survival Rate, Mitochondria, G2 Phase Cell Cycle Checkpoints, Wee1, medicine.anatomical_structure, MESH : Protein Phosphatase 2C, Original Article, MESH : Mitochondria, Colorectal Neoplasms, medicine.drug, MESH : Protein-Serine-Threonine Kinases, MESH: Cell Line, Tumor, MESH: Survival Rate, MESH: Mice, Transgenic, MESH: RNA Interference, Phosphatase, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Protein Serine-Threonine Kinases, Flow cytometry, Cellular and Molecular Neuroscience, Cell Line, Tumor, MESH : Mice, medicine, Animals, MESH: Mice, MESH : Cell Line, Tumor, MESH: Apoptosis, Cell Biology, MESH : Tumor Suppressor Protein p53, MESH: Cisplatin, Cancer research, biology.protein, MESH : Animals, MESH : G2 Phase Cell Cycle Checkpoints, MESH : RNA Interference, Tumor Suppressor Protein p53, MESH: Colorectal Neoplasms, DNA Damage
Abstract: Inactivation of p53 found in more than half of human cancers is often associated with increased tumor resistance to anti-cancer therapy. We have previously shown that overexpression of the phosphatase Wip1 in p53-negative tumors sensitizes them to chemotherapeutic agents, while protecting normal tissues from the side effects of anti-cancer treatment. In this study, we decided to search for kinases that prevent Wip1-mediated sensitization of cancer cells, thereby interfering with efficacy of genotoxic anti-cancer drugs. To this end, we performed a flow cytometry-based screening in order to identify kinases that regulated the levels of γH2AX, which were used as readout. Another criterion of the screen was increased sensitivity of p53-negative tumor cells to cisplatin (CDDP) in a Wip1-dependent manner. We have found that a treatment with a low dose (75 nM) of MK-1775, a recently described specific chemical inhibitor of Wee1, decreases CDDP-induced H2AX phosphorylation in p53-negative cells and enhances the Wip1-sensitization of p53-negative tumors. We were able to reduce CDDP effective concentration by 40% with a combination of Wip1 overexpression and Wee1 kinase inhibition. We have observed that Wee1 inhibition potentiates Wip1-dependent tumor sensitization effect by reducing levels of Hipk2 kinase, a negative regulator of Wip1 pathway. In addition, during CDDP treatment, the combination of Wee1 inhibition and Wip1 overexpression has a mild but significant protective effect in normal cells and tissues. Our results indicate that inhibition of the negative regulators of Wip1 pathway, Wee1 and Hipk2, in p53-negative tumors could potentiate efficiency of chemotherapeutic agents without concomitant increase of cytotoxicity in normal tissues. The development and clinical use of Wee1 and Hipk1 kinase chemical inhibitors might be a promising strategy to improve anti-cancer therapy.
Published: 2016
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9. PPARγ contributes to PKM2 and HK2 expression in fatty liver

Author: Catherine Espeillac, Ganna Panasyuk, Akira Suzuki, Francisco Verdeguer, Lluis Fajas, Céline Chauvin, Jean-Sébastien Annicotte, Marc Foretz, Ludivine A. Pradelli, Jean-Yves Scoazec, Marco Pontoglio, Pascal Ferré, Mario Pende, Morris J. Birnbaum, Jean-Ehrland Ricci, Yasuo Horie, Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anipath, UFR Médecine Lyon-RTH Laennec-UFR Médecine Lyon-RTH Laennec, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, University of Pennsylvania [Philadelphia], Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Pathologies nutritionnelles et métaboliques : obésité et diabète, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the European Research Council, from Fondation de la Recherche Medicale (DEQ20061107956) and from Fondation Schlumberger pour l'Education et la Recherche to M.P., and from the Association pour la Recherche sur le Cancer to M.P. and J.-E.R. L.A.P received a fellowship from the Région Provence-Alpes-Cote-d'Azur and INSERM, C.E. from Ministere de Recherche et Technologies and from Fondation de la Recherche Medicale., We are grateful to the members of INSERM-U845 for support, and to David Sabatini, Stefano Fumagalli, Benoit Viollet, Fabienne Foufelle, Renaud Dentin, Pascal Pineau, Isabelle André-Schmutz, Olivier Danos and Anne Dejean for helpful discussions and sharing reagents. We thank Sophie Berissi, Dominique Chretien and Sylvie Fabrega for technical support., Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Institut de recherche en cancérologie de Montpellier ( IRCM - U896 Inserm - UM1 ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Anipath, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Akita University, Kyushu University, Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tumeurs endocrines digestives : mécanismes de la tumorigenèse et de la progression tumorale, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania, and FORETZ, Marc
Subjects: MESH : Fatty Liver, MESH : Immunohistochemistry, MESH : Insulin, General Physics and Astronomy, Peroxisome proliferator-activated receptor, MESH : Promoter Regions, Genetic, MESH: Thiazolidinediones, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 0302 clinical medicine, Hexokinase, MESH : Cell Proliferation, Insulin, MESH: Hexokinase, MESH: Animals, MESH : Glycolysis, Promoter Regions, Genetic, MESH: Fatty Liver, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, Disease genetics, MESH: Gene Expression Regulation, Enzymologic, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Immunohistochemistry, MESH : Mice, Transgenic, MESH : Thiazolidinediones, MESH : Proto-Oncogene Proteins c-akt, MESH : Thyroid Hormones, Biochemistry, 030220 oncology & carcinogenesis, MESH: Glycolysis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Peroxisome proliferator-activated receptor delta, MESH: Membrane Proteins, Peroxisome proliferator-activated receptor alpha, MESH : Carrier Proteins, Clinical pharmacology, PPARGC1B, Glycolysis, MESH : PPAR gamma, Thyroid Hormones, Peroxisome proliferator-activated receptor gamma, MESH: Mice, Transgenic, Mice, Transgenic, MESH: Carrier Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Insulin, Biology, PKM2, Gene Expression Regulation, Enzymologic, Article, General Biochemistry, Genetics and Molecular Biology, MESH : Gene Expression Regulation, Enzymologic, 03 medical and health sciences, MESH: Thyroid Hormones, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Cell Proliferation, MESH : Mice, MESH: Promoter Regions, Genetic, Animals, Humans, MESH: Mice, Liver diseases, Cell Proliferation, 030304 developmental biology, MESH: Humans, MESH: Proto-Oncogene Proteins c-akt, Liver receptor homolog-1, MESH : Humans, Membrane Proteins, MESH: Immunohistochemistry, General Chemistry, MESH : Hexokinase, Fatty Liver, PPAR gamma, MESH: PPAR gamma, chemistry, MESH : Membrane Proteins, Thiazolidinediones, MESH : Animals, Carrier Proteins, Proto-Oncogene Proteins c-akt, Pyruvate kinase
Abstract: Rapidly proliferating cells promote glycolysis in aerobic conditions, to increase growth rate. Expression of specific glycolytic enzymes, namely pyruvate kinase M2 and hexokinase 2, concurs to this metabolic adaptation, as their kinetics and intracellular localization favour biosynthetic processes required for cell proliferation. Intracellular factors regulating their selective expression remain largely unknown. Here we show that the peroxisome proliferator-activated receptor gamma transcription factor and nuclear hormone receptor contributes to selective pyruvate kinase M2 and hexokinase 2 gene expression in PTEN-null fatty liver. Peroxisome proliferator-activated receptor gamma expression, liver steatosis, shift to aerobic glycolysis and tumorigenesis are under the control of the Akt2 kinase in PTEN-null mouse livers. Peroxisome proliferator-activated receptor gamma binds to hexokinase 2 and pyruvate kinase M promoters to activate transcription. In vivo rescue of peroxisome proliferator-activated receptor gamma activity causes liver steatosis, hypertrophy and hyperplasia. Our data suggest that therapies with the insulin-sensitizing agents and peroxisome proliferator-activated receptor gamma agonists, thiazolidinediones, may have opposite outcomes depending on the nutritional or genetic origins of liver steatosis., Molecular factors, regulating the expression of specific glycolytic enzymes that favour biosynthetic processes, have remained unknown. Panasyuk et al. identify PPARγ as a novel transcription factor turning on pyruvate kinase M2 and hexokinase 2, which are frequently upregulated in pathophysiological growth.
Published: 2012
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10. RANKL induces organized lymph node growth by stromal cell proliferation

Author: S. Lori Bridal, Marion Decossas, Sylvestre Chea, Vincent Duheron, Yongwon Choi, Mattéo R. Bosisio, Frédéric Lézot, Rachel Golub, Christopher G. Mueller, Ariane Berdal, Estelle Hess, Hideo Yagita, Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Lymphopoïèse, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Imagerie Paramétrique (LIP), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Centre National de la Recherche Scientifique (CNRS), ECHOSENS S.A., Echosens, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Department of Immunology, Juntendo University School of Medicine, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia], Immunologie et chimie thérapeutiques ( ICT ), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'Imagerie Paramétrique ( LIP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: MESH: Chemokine CCL19, MESH: Lymph Nodes, MESH : Hair Follicle, Mice, 0302 clinical medicine, MESH : Cell Proliferation, Homeostasis, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, MESH: Animals, Lymph node, MESH : Lymph Nodes, 0303 health sciences, MESH: RANK Ligand, MESH : Mice, Transgenic, MESH : Chemokine CXCL13, Cell biology, medicine.anatomical_structure, Lymphatic system, RANKL, MESH: Homeostasis, MESH : Homeostasis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Hair Follicle, MESH : RANK Ligand, MESH: Chemokine CXCL13, Hair Follicle, Stromal cell, MESH: Mice, Transgenic, Immunology, Mice, Transgenic, Biology, 03 medical and health sciences, MESH: Cell Proliferation, MESH : Mice, medicine, Lymph node stromal cell, Animals, CXCL13, MESH: Mice, B cell, Cell Proliferation, 030304 developmental biology, MESH: Immune System, RANK Ligand, Hair follicle, Chemokine CXCL13, MESH : Chemokine CCL19, Immune System, MESH : Stromal Cells, MESH : Immune System, biology.protein, Chemokine CCL19, Lymph Nodes, MESH : Animals, Stromal Cells, MESH: Stromal Cells, 030215 immunology
Abstract: RANK and its ligand RANKL play important roles in the development and regulation of the immune system. We show that mice transgenic for Rank in hair follicles display massive postnatal growth of skin-draining lymph nodes. The proportions of hematopoietic and nonhematopoietic stromal cells and their organization are maintained, with the exception of an increase in B cell follicles. The hematopoietic cells are not activated and respond to immunization by foreign Ag and adjuvant. We demonstrate that soluble RANKL is overproduced from the transgenic hair follicles and that its neutralization normalizes lymph node size, inclusive area, and numbers of B cell follicles. Reticular fibroblastic and vascular stromal cells, important for secondary lymphoid organ formation and organization, express RANK and undergo hyperproliferation, which is abrogated by RANKL neutralization. In addition, they express higher levels of CXCL13 and CCL19 chemokines, as well as MAdCAM-1 and VCAM-1 cell-adhesion molecules. These findings highlight the importance of tissue-derived cues for secondary lymphoid organ homeostasis and identify RANKL as a key molecule for controlling the plasticity of the immune system.
Published: 2012
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11. Autoimmune mediated regulation of ovarian tumor growth

Author: Vincent K. Tuohy, Cengiz Z. Altuntas, Ritika Jaini, Daniel Jane-wit, Pavani Kesaraju, Christopher A. Flask, Jean Yves Picard, Martin Dutertre, Kelly K Covey, Justin M. Johnson, Lerner Research Institute, Cleveland Clinic, Equipe 7, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Endocrinologie et Génétique de la Reproduction et du Développement, Université Paris-Sud - Paris 11 (UP11)-IFR13-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris-Sud - Paris 11 ( UP11 ) -IFR13-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH : Molecular Sequence Data, endocrine system diseases, Autoimmunity, MESH: Amino Acid Sequence, medicine.disease_cause, HER2/neu, MESH: Cancer Vaccines, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Ovarian tumor, Mice, 0302 clinical medicine, MESH: Autoimmune Diseases, MESH : Autoimmunity, MESH : Female, MESH: Animals, MESH: Peptide Fragments, Ovarian Neoplasms, 0303 health sciences, biology, MESH : Amino Acid Sequence, MESH : Cancer Vaccines, Obstetrics and Gynecology, Anti-Müllerian hormone, MESH : Mice, Transgenic, female genital diseases and pregnancy complications, 3. Good health, Premature ovarian failure, MESH: Ovarian Neoplasms, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, MESH: Cell Growth Processes, Female, endocrine system, MESH: Mice, Transgenic, Molecular Sequence Data, Ovary, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Growth Processes, MESH : Mice, Inbred C57BL, Cancer Vaccines, Article, Autoimmune Diseases, 03 medical and health sciences, Immune system, MESH : Autoimmune Diseases, MESH: Mice, Inbred C57BL, MESH : Mice, MESH: Autoimmunity, medicine, Animals, Humans, Inhibins, Amino Acid Sequence, MESH: Mice, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, MESH : Inhibins, business.industry, MESH : Ovarian Neoplasms, MESH : Peptide Fragments, MESH : Humans, MESH: Inhibins, medicine.disease, MESH : Disease Models, Animal, Peptide Fragments, Mice, Inbred C57BL, Disease Models, Animal, MESH : Cell Growth Processes, Immunology, biology.protein, Cancer vaccine, MESH : Animals, MESH: Disease Models, Animal, business, MESH: Female
Abstract: International audience; OBJECTIVES: An immune response sufficient to induce organ failure may provide protection and therapy against tumors derived from the targeted organ particularly when removal or ablation of the organ is part of the standard therapy and does not threaten survival. We have previously shown that a targeted immune response directed against the ovarian-specific protein, inhibin-α, causes ovarian failure. Here we determined whether inhibin-α autoimmunity is effective in both prevention and treatment of ovarian tumors. METHODS: A transgene consisting of the SV40 large tumor transformation antigen under the regulation of an anti-Mullerian hormone promoter (AMH-SV40Tag) was transferred by backcrossing for 12 generations to SJL/J mice producing SJL.AMH-SV40Tag (H-2(s)) females that develop a high incidence of autochthonous granulosa cell tumors. We determined whether immunization of SJL.AMH-SV40Tag female mice with the IA(s)-restricted p215-234 peptide of mouse inhibin-α was capable of preventing and treating these ovarian tumors. RESULTS: The growth of autochthonous ovarian granulosa cell tumors in SJL.AMH-SV40Tag transgenic mice was significantly inhibited in mice immunized with Inα 215-234. In addition, significant inhibition of tumor growth occurred when mice with established ovarian granulosa cell tumors were therapeutically vaccinated with Inα 215-234. CONCLUSIONS: Our results indicate that induction of ovarian-specific autoimmunity may serve as an effective way to prevent the emergence of autochthonous ovarian tumors and control the growth of established ovarian malignancies.
Published: 2012
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12. Production of human or humanized antibodies in mice

Author: Brice, Laffleur, Virginie, Pascal, Christophe, Sirac, Michel, Cogné, Contrôle de la Réponse Immune B et des Lymphoproliférations ( CRIBL ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Limoges ( UNILIM ), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), and Université de Limoges (UNILIM)
Subjects: MESH: Humans, Genes, Immunoglobulin, MESH: Mice, Transgenic, MESH : Humans, Mice, Transgenic, Antibodies, Monoclonal, Humanized, MESH : Antibodies, Monoclonal, Humanized, MESH : Mice, Transgenic, MESH: Genes, Immunoglobulin, Mice, MESH: Antibodies, Monoclonal, Humanized, MESH : Mice, Animals, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH : Animals, MESH: Mice, MESH : Genes, Immunoglobulin
Abstract: International audience; Mice are widely available laboratory animals that can easily be used for the production of antibodies against a broad range of antigens, using well-defined immunization protocols. Such an approach allows optimal in vivo affinity maturation of the humoral response. In addition, high-affinity antibodies arising in this context can readily be further characterized and produced as monoclonals after immortalizing and selecting specific antibody-producing cells through hybridoma derivation. Using such conventional strategies combined with mice that are either genetically engineered to carry humanized immunoglobulin (Ig) genes or engrafted with a human immune system, it is thus easy to obtain and immortalize clones that produce either fully human Ig or antibodies associating variable (V) domains with selected antigen specificities to customized human-like constant regions, with defined effector functions. In some instances, where there is a need for in vivo functional assays of a single antibody with a known specificity, it might be of interest to transiently express that gene in mice by in vivo gene transfer. This approach allows a rapid functional assay. More commonly, mice are used to obtain a diversified repertoire of antibody specificities after immunization by producing antibody molecules in the mouse B cell lineage from mouse strains with transgene Ig genes which are of human, humanized, or chimeric origin. After in vivo maturation of the immune response, this will lead to the secretion of antibodies with optimized antigen binding sites, associated to the desired human constant domains. This chapter focuses on two simple methods: (1) to obtain such humanized Ig mice and (2) to transiently express a human Ig gene in mice using hydrodynamics-based transfection.
Published: 2012
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13. c-mip down-regulates NF-κB activity and promotes apoptosis in podocytes

Author: Vincent Audard, Marina Candelier, Laure-Hélène Noël, André Pawlak, Georges Guellaen, Nabila Hamdaoui, Dominique Desvaux, Shao-yu Zhang, Philippe Lang, Djillali Sahali, Qingfeng Fan, Virginie Ory, Guellaen, Georges, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'histologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie et transplantation, Institut francilien de recheche en nephrologie et transplantation, IFRNT, This work was supported in part by an Avenir Program from INSERM, a grant from the French Kidney Foundation, Association pour l'Utilisation du Rein Artificiel (AURA), Assistance Publique des Hôpitaux de Paris (AP-HP, Programme hospitalier de recherche clinique) and a grant from the Fondation pour la Recherche Médicale (FRM)., Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12) - Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR10, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Henri Mondor - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Necker - Enfants Malades [AP-HP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
Subjects: Male, MESH : Cell Line, Nephrotic Syndrome, MESH: NF-kappa B, Apoptosis, Idiopathic Nephrotic Syndrome, MESH: Down-Regulation, Podocyte, MESH : Down-Regulation, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Transcription Factor RelA, MESH: Caspase 3, MESH: Up-Regulation, MESH: Microscopy, Confocal, MESH : Caspase 3, MESH: Animals, MESH: In Situ Nick-End Labeling, MESH : Up-Regulation, 0303 health sciences, Microscopy, Confocal, Caspase 3, Podocytes, NF-kappa B, MESH : Adult, MESH : Podocytes, Pathophysiology, MESH : Mice, Transgenic, Up-Regulation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH : NF-kappa B, MESH : In Situ Nick-End Labeling, MESH : Carrier Proteins, Adult, MESH: Mice, Transgenic, MESH : Nephrotic Syndrome, MESH : Male, Down-Regulation, Mice, Transgenic, MESH: Carrier Proteins, Biology, Cell Line, Pathology and Forensic Medicine, 03 medical and health sciences, In vivo, MESH : Mice, MESH: Podocytes, In Situ Nick-End Labeling, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Microscopy, Confocal, MESH: Mice, Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Humans, MESH: Apoptosis, MESH : Transcription Factor RelA, MESH : Humans, Transcription Factor RelA, NF-κB, MESH: Adult, MESH: Male, MESH: Cell Line, Antiapoptotic protein, chemistry, Cancer research, MESH : Animals, MESH: Nephrotic Syndrome, Carrier Proteins, Spatial relationship, MESH : Apoptosis
Abstract: International audience; The mechanisms of podocyte disorders in cases of idiopathic nephrotic syndrome (INS) are complex and remain incompletely elucidated. The abnormal regulation of NF-κB may play a key role in the pathophysiology of these podocyte diseases, but at present, NF-κB has not been thoroughly investigated. In this study, we report that induction of c-mip in podocytes of patients with INS is associated with a down-regulation of RelA, a potent antiapoptotic factor that belongs to the NF-κB family. Overexpression of c-mip in differentiated podocytes promotes apoptosis by inducing caspase-3 activity and up-regulating the proapoptotic protein Bax, whereas the overall levels of the antiapoptotic protein Bcl-2 was concomitantly decreased. The associated overexpression of RelA prevented the proapoptotic effects of c-mip. In addition, the targeted induction of c-mip in podocytes in vivo inhibited the expression of the RelA protein and increased the Bax/Bcl-2 ratio. The expression of both c-mip and active caspase-3 increased in focal and segmental glomerulosclerosis biopsies, and both proteins displayed a close spatial relationship. These results suggest that alterations in NF-κB activity might result from the up-regulation of c-mip and are likely to contribute to podocyte disorders in cases of INS.
Published: 2012
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14. Overexpression of Bcl-2 in hepatocytes protects against injury but does not attenuate fibrosis in a mouse model of chronic cholestatic liver disease

Author: Bernard Fromenty, Claudia Mitchell, Alicia Mayeuf, Abdellah Mansouri, Marie-Anne Robin, Meriem Mahrouf-Yorgov, Hélène Gilgenkrantz, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hépatotoxicité et xénobiotiques, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche biomédicale Bichat-Beaujon ( CRB3 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Necrosis, MESH : Blotting, Western, MESH : Hepatocytes, MESH: Lipid Peroxidation, MESH : Proto-Oncogene Proteins c-bcl-2, necrosis, MESH: Hepatocytes, Mice, 0302 clinical medicine, Fibrosis, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Bile Ducts, MESH: Animals, MESH: In Situ Nick-End Labeling, MESH : Ligation, Liver injury, 0303 health sciences, MESH: Electron Transport Complex I, MESH : Lipid Peroxidation, Reverse Transcriptase Polymerase Chain Reaction, Histological Techniques, MESH : Reverse Transcriptase Polymerase Chain Reaction, apoptosis, Fas receptor, MESH : Mice, Transgenic, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Caspases, Hepatocyte, MESH : In Situ Nick-End Labeling, MESH : Histological Techniques, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030211 gastroenterology & hepatology, medicine.symptom, Programmed cell death, medicine.medical_specialty, MESH: Mice, Transgenic, Blotting, Western, Mice, Transgenic, Cholestasis, Intrahepatic, MESH: Histological Techniques, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Cholestasis, Internal medicine, MESH : Mice, In Situ Nick-End Labeling, medicine, Animals, MESH: Blotting, Western, Bcl-2, Ligation, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Necrosis, Electron Transport Complex I, MESH: Caspases, MESH: Cholestasis, Intrahepatic, MESH: Apoptosis, MESH : Electron Transport Complex I, fibrosis, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, MESH: Ligation, medicine.disease, oxydative stress, MESH : Necrosis, Endocrinology, MESH: Proto-Oncogene Proteins c-bcl-2, Apoptosis, inflammation, Hepatocytes, MESH : Cholestasis, Intrahepatic, Bile Ducts, Lipid Peroxidation, MESH : Animals, MESH : Caspases, MESH: Bile Ducts, cholestasis, MESH : Apoptosis
Abstract: International audience; The role of hepatocyte apoptosis in the physiopathology of obstructive cholestasis is still controversial. Although some data have strongly suggested that hepatocellular cholestatic injury is due to Fas-mediated hepatocyte apoptosis, some others concluded that necrosis, rather than apoptosis, represents the main type of hepatocyte death in chronic cholestasis. Moreover, it has also been suggested that the reduced liver injury observed in the absence of Fas receptor after bile duct ligation was not due to lower hepatocyte apoptosis but to the indirect role of this receptor in non-hepatocytic cells such as cholangiocytes and inflammatory cells. The aim of this work was therefore to determine whether a protection against cell death limited to hepatocytes could be sufficient to reduce liver injury and delay cholestatic fibrosis. With this purpose, we performed bile duct ligation in transgenic mice overexpressing Bcl-2 in hepatocytes and in wild-type littermates. We found that, compared with necrosis, apoptosis was negligible in this model. Our results also showed that hepatocyte Bcl-2 expression protected hepatocytes against liver injury only in the early steps of the disease. This protection was correlated with reduced mitochondrial dysfunction and lipid peroxidation. However, in contrast to Fas receptor-deficient lpr mice, fibrosis progression was not hampered and liver inflammatory response was not reduced by Bcl-2 overexpression. These results therefore comfort the hypothesis that Fas-mediated apoptotic hepatocyte pathway is not a significant contributing factor to the clinical features observed in cholestasis. Moreover, in the absence of a blunted inflammatory response in transgenic mice, Bcl-2 protection against hepatocyte mitochondrial dysfunction and lipid peroxidation was not sufficient to block fibrosis progression.
Published: 2011
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15. Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia

Author: Damien Grapton, Marie-Alexandra Alyanakian, Virginie Pascal, Michael Dussiot, Tomas Leanderson, Thiago Trovati Maciel, Olivier Hermine, Marc Benhamou, Séverine Coulon, Renato C. Monteiro, Patrick Mayeux, Kamel Djedaini, Zeliha Oruc, Julie Vandekerckhove, Saurabh Agarwal, Meetu Kaushik Tiwari, Michel Cogné, Ivan C. Moura, Bertrand Arnulf, Houda Tamouza, Geneviève Courtois, Aurélie Fricot, Pamella Huey Mei Wang, Yael Zermati, Jean-Antoine Ribeil, Céline Callens, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Immunopathologie rénale, récepteurs et inflammation, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation des cellules B, hémopathies, lymphoïdes et déficit de l'immunité humorale, Université Paris Diderot - Paris 7 (UPD7), Tolérance immunitaire et présentation antigénique: impact en auto-immunité et en transplantation, Institut Cochin (UMR_S567 / UMR 8104), Université de Limoges (UNILIM), Service d Hématologie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 ( UPD5 ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations ( PMRIL ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Diderot - Paris 7 ( UPD7 ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université de Limoges ( UNILIM ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), and Slama, Catherine
Subjects: Ineffective erythropoiesis, MESH: Signal Transduction, MESH: Anemia, Erythroblasts, MESH: Mice, Inbred NOD, MESH: Anoxia, Mice, SCID, medicine.disease_cause, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Mice, Inbred NOD, hemic and lymphatic diseases, MESH : Cell Proliferation, MESH : Erythropoietin, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Erythropoiesis, MESH: Animals, MESH: Mice, SCID, MESH: Erythroblasts, Hypoxia, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, 0303 health sciences, Transferrin, Anemia, General Medicine, MESH : Transferrin, MESH : Mice, Transgenic, 3. Good health, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Mitogen-Activated Protein Kinases, MESH: Transferrin, medicine.drug, Signal Transduction, MESH: Cells, Cultured, MESH : Anoxia, MESH: Mice, Transgenic, MESH : Anemia, Transferrin receptor, Mice, Transgenic, MESH : Immunoglobulin A, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, MESH : Erythropoiesis, Erythroblast, MESH: Cell Proliferation, Receptors, Transferrin, MESH : Mice, MESH : Cells, Cultured, medicine, Animals, Humans, MESH : Receptors, Transferrin, MESH: Receptors, Transferrin, MESH: Erythropoietin, MESH: Immunoglobulin A, Erythropoietin, MESH: Mice, PI3K/AKT/mTOR pathway, 030304 developmental biology, Cell Proliferation, MESH : Signal Transduction, MESH: Humans, MESH : Mice, Inbred NOD, MESH : Humans, MESH: Erythropoiesis, MESH : Mitogen-Activated Protein Kinases, MESH : Phosphatidylinositol 3-Kinases, MESH : Erythroblasts, medicine.disease, MESH: Mitogen-Activated Protein Kinases, MESH : Mice, SCID, Immunoglobulin A, chemistry, MESH: Phosphatidylinositol 3-Kinases, Immunology, Cancer research, MESH : Animals
Abstract: International audience; Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXΦ. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.
Published: 2011
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16. PPARα activation differently affects microparticle content in atherosclerotic lesions and liver of a mouse model of atherosclerosis and NASH

Author: Aurélie S. Leroyer, Anne Tailleux, Philippe Delerive, Emmanuelle Vallez, Morgane Baron, Fanny Lalloyer, Kadiombo Bantubungi, Chantal M. Boulanger, Bart Staels, Zouher Majd, Giulia Chinetti-Gbaguidi, Derudas, Marie-Hélène, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genfit, Entreprise biopharmaceutique GENFIT Loos, This work was supported by grants of EU grant Hepadip 018734, the Foundation Coeur et Artères and Région Nord-Pas de Calais / FEDER, Récepteurs nucléaires, maladies cardiovasculaires et diabète ( EGID ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: Pathology, MESH : Fatty Liver, MESH : Atherosclerosis, MESH : Cell-Derived Microparticles, MESH: Flow Cytometry, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, murine model, MESH: Atherosclerosis, Mice, 0302 clinical medicine, Fenofibrate, Cell-Derived Microparticles, Non-alcoholic Fatty Liver Disease, MESH: Cell-Derived Microparticles, MESH : Female, MESH: Animals, MESH: PPAR alpha, MESH: Fatty Liver, Mice, Knockout, microparticles, 0303 health sciences, medicine.diagnostic_test, Fatty liver, Flow Cytometry, MESH : Mice, Transgenic, Liver, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, MESH : Flow Cytometry, MESH: Mice, Transgenic, Transgene, MESH : PPAR alpha, Inflammation, Mice, Transgenic, MESH : Mice, Inbred C57BL, Biology, Flow cytometry, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Mice, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, PPAR alpha, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH : Humans, MESH: Biological Markers, MESH : Liver, nutritional and metabolic diseases, medicine.disease, MESH: Fenofibrate, MESH : Disease Models, Animal, Fatty Liver, Mice, Inbred C57BL, MESH : Biological Markers, Disease Models, Animal, Endocrinology, Nuclear receptor, Apoptosis, MESH : Mice, Knockout, fatty liver disease, MESH : Animals, Steatohepatitis, atherosclerosis, pharmacology, MESH: Disease Models, Animal, MESH : Fenofibrate, MESH: Female, Biomarkers, MESH: Liver
Abstract: International audience; BACKGROUND: Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are complex pathologies characterized by lipid accumulation, chronic inflammation and extensive tissue remodelling. Microparticles (MPs), small membrane vesicles produced by activated and apoptotic cells, might not only be biomarkers, but also functional actors in these pathologies. The apoE2-KI mouse is a model of atherosclerosis and NAFLD. Activation of the nuclear receptor PPARα decreases atherosclerosis and components of non-alcoholic steatohepatitis (NASH) in the apoE2-KI mouse. OBJECTIVES: (1) To determine whether MPs are present in atherosclerotic lesions, liver and plasma during atherosclerosis and NASH progression in apoE2-KI mice, and (2) to study whether PPARα activation modulates MP concentrations. METHODS: ApoE2-KI mice were fed a Western diet to induce atherosclerosis and NASH. MPs were isolated from atherosclerotic lesions, liver and blood and quantified by flow cytometry. RESULTS: An increase of MPs was observed in the atherosclerotic lesions and in the liver of apoE2-KI mice upon Western diet feeding. PPARα activation with fenofibrate decreased MP levels in the atherosclerotic lesions in a PPARα-dependent manner, but did not influence MP concentrations in the liver. CONCLUSION: Here we report that MPs are present in atherosclerotic lesions and in the liver of apoE2-KI mice. Their concentration increased during atherosclerosis and NASH development. PPARα activation differentially modulates MP levels in a tissue-specific manner.
Published: 2011
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17. IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis

Author: Lizette Fick, Rachel Vacher, Alain Fautrel, Maria Leite-de-Moraes, Isabelle Couillin, Bernhard Ryffel, Sabine Charron, Paméla Gasse, Marc Le Bert, Marie-Laure Michel, François Huaux, Gérard Eberl, Nicolas Riteau, Vincent Lagente, Valérie F. J. Quesniaux, Franco Di Padova, Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hépatotoxicité et xénobiotiques, Plate-forme d'histopathologie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Novartis Pharma AG, Institute of Immunology and Infectious Disease and Molecular Medicine, Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Développement des Tissus Lymphoïdes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain = Catholic University of Louvain (UCL), UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, Brébion, Alice, Université de Rennes (UR)-Université de Rennes (UR)-Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Couillin, Isabelle, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, Immunologie et embryologie moléculaires (IEM), Immunologie et embryologie moléculaires ( IEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Foie, métabolismes et cancer, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Microenvironnement et remodelage, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Université Catholique de Louvain ( UCL ), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), and Université d'Orléans (UO) - Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Pulmonology, MESH: Flow Cytometry, MESH : Interleukin-23 Subunit p19, Idiopathic pulmonary fibrosis, Mice, MESH : Bleomycin, 0302 clinical medicine, Fibrosis, T-Lymphocyte Subsets, MESH: Interleukin-1beta, Pulmonary fibrosis, Interleukin 23, MESH: Animals, Immune Response, Lung, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH : Reverse Transcriptase Polymerase Chain Reaction, Lung Injury, Flow Cytometry, MESH : Enzyme-Linked Immunosorbent Assay, MESH : Mice, Transgenic, MESH: Bleomycin, 3. Good health, Medicine, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Immune Cells, Science, Immunology, Bleomycin, MESH : Interleukin-1beta, 03 medical and health sciences, Biology, MESH : Pneumonia, Immunity, Pneumonia, medicine.disease, MESH : T-Lymphocyte Subsets, Mice, Inbred C57BL, chemistry, Interleukin-23 Subunit p19, MESH : Transforming Growth Factor beta1, MESH: Female, Neutrophils, Pulmonary Fibrosis, MESH: Interleukin-17, Interleukin-1beta, MESH: T-Lymphocyte Subsets, Inflammatory diseases, Interleukin-23, MESH: Mice, Knockout, chemistry.chemical_compound, MESH: Transforming Growth Factor beta1, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Lung Injury, MESH : Female, Enzyme-linked immunoassays, Mice, Knockout, MESH: Interleukin-23, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Interleukin-17, MESH: Enzyme-Linked Immunosorbent Assay, medicine.anatomical_structure, MESH: Lung Injury, Female, medicine.symptom, Research Article, MESH: Pneumonia, MESH : Flow Cytometry, MESH: Mice, Transgenic, MESH : Male, MESH : Lung, T cells, Inflammation, Mice, Transgenic, Enzyme-Linked Immunosorbent Assay, MESH: Interleukin-23 Subunit p19, MESH : Mice, Inbred C57BL, MESH : Interleukin-17, Immunopathology, Lung injury, Interstitial Lung Diseases, MESH : Pulmonary Fibrosis, Transforming Growth Factor beta1, MESH: Mice, Inbred C57BL, MESH : Mice, medicine, Animals, MESH: Lung, MESH: Mice, 030304 developmental biology, MESH: Pulmonary Fibrosis, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, MESH : Interleukin-23, MESH : Mice, Knockout, MESH : Animals, Collagens, 030215 immunology
Abstract: BackgroundIdiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice.MethodsThe contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice.ResultsWe show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt(+) γδ T cells and to a lesser extent by CD4αβ(+) T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis.ConclusionsOur findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology.
Published: 2011
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18. Relationships between adipose tissues and brain: what do we learn from animal studies?

Author: Luc Pénicaud, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), and Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS )
Subjects: medicine.medical_specialty, MESH: Mice, Transgenic, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Diabetes and Metabolism, Central nervous system, Adipokine, Adipose tissue, Mice, Transgenic, White adipose tissue, Biology, MESH : Adipose Tissue, Energy homeostasis, Mice, MESH: Brain, Endocrinology, MESH : Lipid Metabolism, Internal medicine, MESH : Mice, Brown adipose tissue, Internal Medicine, medicine, Animals, Humans, Lipolysis, MESH: Animals, MESH: Mice, MESH: Lipid Metabolism, MESH: Humans, Leptin, MESH : Humans, Brain, General Medicine, Lipid Metabolism, MESH : Mice, Transgenic, MESH : Models, Animal, medicine.anatomical_structure, Adipose Tissue, MESH : Brain, MESH: Models, Animal, Models, Animal, MESH : Animals, Neuroscience, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: Adipose Tissue
Abstract: International audience; Over the last decades, more and more data supporting the importance of the relationships between the brain and adipose tissues (white and brown) in regards of body weight regulation and energy homeostasis have been published. Indeed the brain via the autonomic nervous system participates to the regulation of different parameters such as the metabolic (lipolysis, lipogenesis and thermogeneis), and secretory (leptin and other adipokines) activities but also plasticity (proliferation differentiation and apoptosis) of adipose tissues. In turn the various fat pads will send information via sensory innervation of white adipose tissue as well as metabolic and hormonal signals acting directly on some brain areas. Altogether these results showed the presence of a neural feedback loop between adipose tissues and the brain which plays a major role in the regulation of energy homeostasis and as been shown to vary according to physiological and pathological states.
Published: 2010
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19. Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons

Author: Françoise Helmbacher, Yang Liu, Igor M. Samokhvalov, Lise Rodat-Despoix, Patrick Delmas, Eduardo Gascon, Pascale Malapert, Aziz Moqrich, Stéphane Gaillard, Flavio Maina, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-06-NEUR-0039,OlfLocalTrans,Traduction locale axonale et dendritique dans le développement et le renouvellement du système olfactif(2006), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), and ANR-06-NEURO-0039,OlfLocalTrans,Traduction locale axonale et dendritique dans le développement et le renouvellement du système olfactif ( 2006 )
Subjects: MESH: Hepatocyte Growth Factor, MESH: Signal Transduction, Cellular differentiation, MESH : Neuropeptides, MESH: Proto-Oncogene Proteins c-met, MESH: Neuropeptides, MESH : Nociceptors, MESH: Mice, Knockout, Mice, 0302 clinical medicine, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Ganglia, Spinal, hemic and lymphatic diseases, MESH: Animals, MESH: Nociceptors, Receptor, Cells, Cultured, Mice, Knockout, 0303 health sciences, education.field_of_study, Hepatocyte Growth Factor, General Neuroscience, Nociceptors, Cell Differentiation, Articles, Proto-Oncogene Proteins c-met, MESH : Mice, Transgenic, Core Binding Factor Alpha 2 Subunit, embryonic structures, Nociceptor, Hepatocyte growth factor, MESH: Ganglia, Spinal, Signal transduction, MESH : Cell Differentiation, Signal Transduction, medicine.drug, MESH: Cells, Cultured, MESH : Core Binding Factor Alpha 2 Subunit, MESH: Cell Differentiation, MESH : Proto-Oncogene Proteins c-met, MESH: Mice, Transgenic, Models, Neurological, Population, Neuropeptide, MESH : Cell Lineage, Mice, Transgenic, Calcitonin gene-related peptide, Biology, 03 medical and health sciences, MESH: Models, Neurological, MESH : Mice, MESH : Cells, Cultured, medicine, Animals, MESH : Models, Neurological, Cell Lineage, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], education, MESH: Mice, 030304 developmental biology, MESH : Signal Transduction, Neuropeptides, MESH: Cell Lineage, MESH: Core Binding Factor Alpha 2 Subunit, MESH : Ganglia, Spinal, MESH : Hepatocyte Growth Factor, nervous system, MESH : Mice, Knockout, MESH : Animals, Neuroscience, 030217 neurology & neurosurgery
Abstract: Nociceptors in peripheral ganglia display a remarkable functional heterogeneity. They can be divided into the following two major classes: peptidergic and nonpeptidergic neurons. Although RUNX1 has been shown to play a pivotal role in the specification of nonpeptidergic neurons, the mechanisms driving peptidergic differentiation remain elusive. Here, we show that hepatocyte growth factor (HGF)-Met signaling acts synergistically with nerve growth factor-tyrosine kinase receptor A to promote peptidergic identity in a subset of prospective nociceptors. We providein vivoevidence that a population of peptidergic neurons, derived from the RUNX1 lineage, require Met activity for the proper extinction ofRunx1and optimal activation ofCGRP(calcitonin gene-related peptide). Moreover, we show that RUNX1 in turn represses Met expression in nonpeptidergic neurons, revealing a bidirectional cross talk between Met and RUNX1. Together, our novel findings support a model in which peptidergic versus nonpeptidergic specification depends on a balance between HGF-Met signaling andRunx1extinction/maintenance.
Published: 2010
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20. Sublingual immunization with an HIV subunit vaccine induces antibodies and cytotoxic T cells in the mouse female genital tract

Author: Fabienne Anjuère, Carmelo Luci, Concepción Marañón, Nicolas Çuburu, Catherine Hervouet, Anne Hosmalin, Cecil Czerkinsky, Lene Vimeux, Selma Bekri, Magali Cremel, Biologie et physiopathologie cutanées : expression génique, signalisation et thérapie, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité muqueuse et vaccination, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA) - IFR50 - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR50 - Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM) - Aix Marseille Université (AMU) - Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: MESH: HIV Envelope Protein gp41, HIV Infections, HIV Antibodies, Mice, 0302 clinical medicine, Cytotoxic T cell, MESH : Female, MESH: Animals, MESH : Mucous Membrane, MESH : Administration, Sublingual, AIDS Vaccines, MESH: Immunoglobulin G, Mice, Inbred BALB C, 0303 health sciences, biology, MESH: Dendritic Cells, virus diseases, Genitalia, Female, MESH: HIV Infections, MESH : Mice, Transgenic, HIV Envelope Protein gp41, 3. Good health, Vaccination, MESH : Genitalia, Female, Infectious Diseases, medicine.anatomical_structure, MESH: Administration, Sublingual, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Antibody, MESH : Immunoglobulin G, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Cross-Priming, MESH : AIDS Vaccines, MESH: Mice, Transgenic, T cell, Administration, Sublingual, MESH: Mice, Inbred BALB C, MESH : Immunoglobulin A, Mice, Transgenic, MESH : Mice, Inbred C57BL, Gp41, Virus, MESH : T-Lymphocytes, Cytotoxic, MESH : HIV Antibodies, 03 medical and health sciences, Cross-Priming, Immune system, MESH: AIDS Vaccines, MESH: Mice, Inbred C57BL, MESH : Mice, MESH : Cross-Priming, MESH : HIV Infections, medicine, Animals, Humans, MESH: Immunoglobulin A, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, Mucous Membrane, MESH: Humans, General Veterinary, General Immunology and Microbiology, MESH: HIV Antibodies, MESH : Humans, Public Health, Environmental and Occupational Health, MESH: Mucous Membrane, Dendritic Cells, Virology, Immunoglobulin A, Mice, Inbred C57BL, MESH : HIV Envelope Protein gp41, Immunization, MESH : Dendritic Cells, Immunoglobulin G, Immunology, biology.protein, MESH : Animals, MESH: Genitalia, Female, MESH: T-Lymphocytes, Cytotoxic, MESH: Female, T-Lymphocytes, Cytotoxic, 030215 immunology
Abstract: International audience; A vaccine against heterosexual transmission by human immunodeficiency virus (HIV) should generate cytotoxic and antibody responses in the female genital tract and in extra-genital organs. We report that sublingual immunization with HIV-1 gp41 and a reverse transcriptase polypeptide coupled to the cholera toxin B subunit (CTB) induced gp41-specific IgA antibodies and antibody-secreting cells, as well as reverse transcriptase-specific CD8 T cells in the genital mucosa, contrary to intradermal immunization. Conjugation of the reverse transcriptase peptide to CTB favored its cross-presentation by human dendritic cells to a T cell line from an HIV(+) patient. Sublingual vaccination could represent a promising vaccine strategy against heterosexual transmission of HIV-1.
Published: 2010
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21. Cellular in vivo imaging reveals coordinated regulation of pituitary microcirculation and GH cell network function

Author: M. Fernandez-Fuente, Gérard Mennessier, Helen C. Christian, Chrystel Lafont, Alain Lacampagne, Danielle Carmignac, Mathieu Cassou, Pierre Fontanaud, Paul Le Tissier, Patrice Mollard, David J. Hodson, Taoufik El Yandouzi, Iain C. A. F. Robinson, François Molino, Michel G. Desarménien, Serge Charpak, Jérôme Lecoq, Nathalie Coutry, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Neurophysiologie et nouvelles microscopies (NNM (UM 82)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Physiopathologie cardiovasculaire, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physique Théorique et Astroparticules (LPTA), Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Neurophysiologie et nouvelles microscopies ( NNM (UM 82) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Physique Théorique et Astroparticules ( LPTA ), and Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Male, Pituitary gland, medicine.medical_specialty, MESH: Mice, Transgenic, MESH : Male, MESH: Pituitary Gland: blood supply,cytology,metabolism, 030209 endocrinology & metabolism, Context (language use), Mice, Transgenic, MESH : Mice, Inbred C57BL, Biology, MESH : Microcirculation, Microcirculation, 03 medical and health sciences, Mice, 0302 clinical medicine, MESH: Mice, Inbred C57BL, Internal medicine, [ INFO.INFO-BI ] Computer Science [cs]/Bioinformatics [q-bio.QM], Parenchyma, MESH : Mice, MESH: Growth Hormone: metabolism, MESH: Microcirculation, medicine, Extracellular, Animals, MESH: Animals, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Mice, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Biological Sciences, MESH : Growth Hormone: metabolism, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Growth hormone secretion, MESH : Mice, Transgenic, MESH: Male, Mice, Inbred C57BL, medicine.anatomical_structure, Endocrinology, Growth Hormone, Pituitary Gland, Secretagogue, MESH : Animals, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH : Pituitary Gland: blood supply,cytology,metabolism, Hormone
Abstract: Growth hormone (GH) exerts its actions via coordinated pulsatile secretion from a GH cell network into the bloodstream. Practically nothing is known about how the network receives its inputs in vivo and releases hormones into pituitary capillaries to shape GH pulses. Here we have developed in vivo approaches to measure local blood flow, oxygen partial pressure, and cell activity at single-cell resolution in mouse pituitary glands in situ. When secretagogue (GHRH) distribution was modeled with fluorescent markers injected into either the bloodstream or the nearby intercapillary space, a restricted distribution gradient evolved within the pituitary parenchyma. Injection of GHRH led to stimulation of both GH cell network activities and GH secretion, which was temporally associated with increases in blood flow rates and oxygen supply by capillaries, as well as oxygen consumption. Moreover, we observed a time-limiting step for hormone output at the perivascular level; macromolecules injected into the extracellular parenchyma moved rapidly to the perivascular space, but were then cleared more slowly in a size-dependent manner into capillary blood. Our findings suggest that GH pulse generation is not simply a GH cell network response, but is shaped by a tissue microenvironment context involving a functional association between the GH cell network activity and fluid microcirculation.
Published: 2010
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22. Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes

Author: Tim Sparwasser, Alexandre Boissonnas, Luc Fetler, Alix Scholer-Dahirel, Bernard Malissen, Adrien Kissenpfennig, Luigia Pace, Fabien Valet, Virginie Simon-Blancal, Sebastian Amigorena, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hannover Medical School [Hannover] (MHH), Physico-Chimie-Curie (PCC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Hannover Medical School [Hannover] ( MHH ), Physico-Chimie-Curie ( PCC ), and Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC )
Subjects: MESH: Cell Death, MESH : Fibrosarcoma, Fibrosarcoma, Priming (immunology), MESH: Lymph Nodes, MESH: T-Lymphocyte Subsets, Lymphocyte Activation, T-Lymphocytes, Regulatory, MESH: Mice, Knockout, MESH : T-Lymphocytes, Regulatory, Interleukin 21, Mice, 0302 clinical medicine, Cell Movement, T-Lymphocyte Subsets, MESH : Cell Movement, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Cytotoxic T cell, MESH : Female, MESH: Animals, MOLIMMUNO, MESH: Cell Movement, MESH : Lymph Nodes, Mice, Knockout, 0303 health sciences, Cell Death, MESH: Dendritic Cells, MESH: Fibrosarcoma, Forkhead Transcription Factors, hemic and immune systems, MESH : Mice, Transgenic, 3. Good health, MESH : Forkhead Transcription Factors, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Cell Line, Tumor, MESH: Mice, Transgenic, T cell, Immunology, Mice, Transgenic, chemical and pharmacologic phenomena, MESH : Mice, Inbred C57BL, Biology, TREG CELLS, MESH: Cell Adhesion, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Forkhead Transcription Factors, Cell Line, Tumor, MESH : Mice, medicine, Lymph node stromal cell, Cell Adhesion, MESH : Neoplasm Transplantation, Animals, MESH : Perforin, Antigen-presenting cell, MESH: Lymphocyte Activation, MESH: Mice, MESH : Lymphocyte Activation, 030304 developmental biology, MESH : Cell Line, Tumor, Perforin, MESH: T-Lymphocytes, Regulatory, Dendritic cell, Dendritic Cells, MESH : T-Lymphocyte Subsets, MESH: Perforin, Mice, Inbred C57BL, MESH : Cell Adhesion, CELLIMMUNO, MESH : Cell Death, MESH : Dendritic Cells, Cancer research, MESH : Mice, Knockout, MESH : Animals, Lymph Nodes, MESH: Female, CD8, Neoplasm Transplantation, MESH: Neoplasm Transplantation, 030215 immunology
Abstract: International audience; Regulatory T (Treg) cells limit the onset of effective antitumor immunity, through yet-ill-defined mechanisms. We showed the rejection of established ovalbumin (OVA)-expressing MCA101 tumors required both the adoptive transfer of OVA-specific CD8(+) T cell receptor transgenic T cells (OTI) and the neutralization of Foxp3(+) T cells. In tumor-draining lymph nodes, Foxp3(+) T cell neutralization induced a marked arrest in the migration of OTI T cells, increased numbers of dendritic cells (DCs), and enhanced OTI T cell priming. Using an in vitro cytotoxic assay and two-photon live microscopy after adoptive transfer of DCs, we demonstrated that Foxp3(+) T cells induced the death of DCs in tumor-draining lymph nodes, but not in the absence of tumor. DC death correlated with Foxp3(+) T cell-DC contacts, and it was tumor-antigen and perforin dependent. We conclude that Foxp3(+) T cell-dependent DC death in tumor-draining lymph nodes limits the onset of CD8(+) T cell responses.
Published: 2010
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23. Autophosphorylation-independent and -dependent functions of focal adhesion kinase during development

Author: Corsi, Jean-Marc, Houbron, Christophe, Billuart, Pierre, Brunet, Isabelle, Bouvrée, Karine, Eichmann, Anne, Girault, Jean-Antoine, Enslen, Hervé, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Angiogénèse embryonnaire et pathologique, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), ARC 3746, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Mutation, MESH: Mice, Transgenic, MESH : Male, proliferation, MESH : Focal Adhesion Protein-Tyrosine Kinases, MESH : Mice, Inbred C57BL, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Cell Adhesion, MESH : Phosphorylation, vascularization, MESH: Mice, Inbred C57BL, MESH : Mice, MESH : Embryo, Mammalian, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, development, MESH: Mice, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Focal Adhesion Protein-Tyrosine Kinases, MESH: Phosphorylation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Biological Markers, MESH: Embryo, Mammalian, tyrosine kinase, MESH: Integrins, MESH : Mice, Transgenic, MESH: Male, MESH : Biological Markers, MESH : Cell Adhesion, Adhesion, MESH : Animals, MESH : Mutation, MESH : Integrins
Abstract: International audience; Focal adhesion kinase (FAK) regulates numerous cellular functions and is critical for processes ranging from embryo development to cancer progression. Although autophosphorylation on Tyr-397 appears required for FAK functions in vitro, its role in vivo has not been established. We addressed this question using a mutant mouse (fakDelta) deleted of exon 15, which encodes Tyr-397. The resulting mutant protein FAKDelta is an active kinase expressed at normal levels. Our results demonstrate that the requirement for FAK autophosphorylation varies during development. FAK(Delta/Delta) embryos developed normally up to embryonic day (E) 12.5, contrasting with the lethality at E8.5 of FAK-null embryos. Thus, autophosphorylation on Tyr-397 is not required for FAK to achieve its functions until late mid-gestation. However, FAK(Delta/Delta) embryos displayed hemorrhages, edema, delayed artery formation, vascular remodeling defects, multiple organ abnormalities, and overall developmental retardation at E13.5-14.5, and died thereafter demonstrating that FAK autophosphorylation is also necessary for normal development. Fibroblasts derived from mutant embryos had a normal stellate morphology and expression of focal adhesion proteins, Src family members, p53, and Pyk2. In contrast, in FAK(Delta/Delta) fibroblasts and endothelial cells, spreading and lamellipodia formation were altered with an increased size and number of focal adhesions, enriched in FAKDelta. FAK mutation also decreased fibroblast proliferation. These results show that the physiological functions of FAK in vivo are achieved through both autophosphorylation-independent and autophosphorylation-dependent mechanisms.
Published: 2009
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24. Design of a HIV-1-derived HLA-B07.02-restricted polyepitope construct

Author: François Lemonnier, Sophie Tourdot, Romain Bouziat, Pierre-Simon Rohrlich, Laurence Weiss, Pierre Langlade-Demoyen, Peter van Endert, Sylvain Cardinaud, Susana Fiorentino, Anne Burgevin, Immunité Cellulaire Antivirale, Institut Pasteur [Paris] (IP), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Diabète de Type 1 : mécanismes et traitements immunologiques, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Institut Pasteur [Paris], Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Cytotoxicity, Immunologic, MESH : Cytotoxicity, Immunologic, Epitopes, T-Lymphocyte, MESH: Mice, Knockout, Epitope, MESH: HIV-1, Mice, 0302 clinical medicine, Vaccines, DNA, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Cytotoxic T cell, MESH: Animals, Antigens, Viral, AIDS Vaccines, Mice, Knockout, 0303 health sciences, Immunogenicity, ELISPOT, MESH : Mice, Transgenic, 3. Good health, Infectious Diseases, medicine.anatomical_structure, MESH : HLA-B Antigens, MESH: Oligopeptides, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Antigens, Viral, Oligopeptides, MESH : HIV-1, MESH : Oligopeptides, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : AIDS Vaccines, MESH: Mice, Transgenic, T cell, Immunology, Antigen presentation, Mice, Transgenic, Human leukocyte antigen, Biology, MESH : T-Lymphocytes, Cytotoxic, MESH: Epitopes, T-Lymphocyte, 03 medical and health sciences, HLA-B7 Antigen, MESH: AIDS Vaccines, Antigen, MESH : Mice, medicine, Animals, MESH: Cytotoxicity, Immunologic, MESH : Epitopes, T-Lymphocyte, MESH: Mice, 030304 developmental biology, MESH : Antigens, Viral, Virology, MESH: Vaccines, DNA, HLA-B Antigens, MESH : Vaccines, DNA, HIV-1, MESH: HLA-B Antigens, MESH : Mice, Knockout, MESH : Animals, MESH: T-Lymphocytes, Cytotoxic, 030215 immunology, T-Lymphocytes, Cytotoxic
Abstract: International audience; OBJECTIVE: To design a vaccine construct containing various but conserved HIV-1-derived epitopes and generating broad CD8 T cell responses. METHODS: HLA-B7 transgenic H-2KD KO transgenic mice were used to identify potential new HLA-B07.02-restricted HIV-1-derived epitopes. Immunological recognition of these epitopes was confirmed by IFN-gamma ELISpot assays with PBMCs from HLA-B*0702 HIV-1-infected individuals. For these peptides as well as others previously identified, the capacity to induce cross-reactive responses against their frequent allelic variants was evaluated in the mouse model. A set of epitopes inducing strong T cell responses against various and conserved regions of HIV-1 was selected. A DNA vaccine was designed to express them as a unique antigen with or without a three amino acid ARY extension flanking each epitope. The spectrum of CD8 T responses generated by polyepitope constructs was tested in HLA-B7 transgenic mice. RESULTS: Five new epitopes were identified in accessory and regulatory HIV-1 proteins. Twelve HLA-B07.02-restricted epitopes were selected on the basis of their structural conservation and cross-reactive immunogenicity. The ARY N-terminal extension flanking each epitope markedly increases their affinity for TAP and the use of this flanking extension in polyepitope vaccine has a sizable advantage to induce CD8 T cell cytotoxic responses in mice following DNA immunization. CONCLUSION: The HLA-B7 mouse model allows to rapidly identify various HIV-1-derived epitopes of vaccine interest. Grouped in a polyepitope construct designed to increase their processing, this vaccine may be suitable for inducing multiple and relevant HIV-1-specific CTL responses in humans.
Published: 2009
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25. iNKT cell development is orchestrated by different branches of TGF-beta signaling

Author: Sylvie Martel, C Garcia, Régine Losson, Jean-Marc Doisne, Farhan S. Cyprian, Nadia Duarte, Kamel Benlagha, Kai-Ping Yan, Jean-Benoît Le Luduec, Laurent Bartholin, Julien C. Marie, Branka Horvat, David F. Vincent, Ruth Rimokh, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP], Immunologie, génétique et traitement des maladies métaboliques et du diabète ( UMR_S 561 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), École normale supérieure - Lyon ( ENS Lyon ) -IFR128-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunité infection vaccination ( I2V ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), and Peney, Maité
Subjects: MESH: Signal Transduction, MESH : Transcription Factors, MESH : Receptors, Transforming Growth Factor beta, MESH: Spleen, Cellular differentiation, Apoptosis, MESH: T-Lymphocyte Subsets, Mice, 0302 clinical medicine, T-Lymphocyte Subsets, Transforming Growth Factor beta, MESH: Smad4 Protein, Immunology and Allergy, MESH: Animals, Smad4 Protein, 0303 health sciences, biology, Stem Cells, Cell Differentiation, MESH: Transcription Factors, Natural killer T cell, MESH : Mice, Transgenic, Cell biology, MESH: Interleukin-2 Receptor beta Subunit, MESH : Stem Cells, MESH: Receptors, Transforming Growth Factor beta, Stem cell, Signal transduction, MESH : Cell Differentiation, Signal Transduction, MESH : Spleen, MESH: Cell Differentiation, MESH: T-Box Domain Proteins, MESH: Mice, Transgenic, Immunology, MESH : Cell Lineage, Mice, Transgenic, MESH: Stem Cells, Article, 03 medical and health sciences, MESH : Mice, TGF beta signaling pathway, Animals, Cell Lineage, Transcription factor, MESH: Mice, MESH: Transforming Growth Factor beta, MESH : Interleukin-2 Receptor beta Subunit, 030304 developmental biology, MESH : Signal Transduction, Cell growth, MESH: Apoptosis, MESH : Smad4 Protein, Transforming growth factor beta, MESH: Cell Lineage, MESH : Natural Killer T-Cells, MESH : T-Lymphocyte Subsets, Interleukin-2 Receptor beta Subunit, MESH : T-Box Domain Proteins, MESH : Transforming Growth Factor beta, MESH: Natural Killer T-Cells, biology.protein, Natural Killer T-Cells, MESH : Animals, T-Box Domain Proteins, Receptors, Transforming Growth Factor beta, Spleen, MESH : Apoptosis, Transcription Factors, 030215 immunology
Abstract: International audience; Invariant natural killer T (iNKT) cells constitute a distinct subset of T lymphocytes exhibiting important immune-regulatory functions. Although various steps of their differentiation have been well characterized, the factors controlling their development remain poorly documented. Here, we show that TGF-beta controls the differentiation program of iNKT cells. We demonstrate that TGF-beta signaling carefully and specifically orchestrates several steps of iNKT cell development. In vivo, this multifaceted role of TGF-beta involves the concerted action of different pathways of TGF-beta signaling. Whereas the Tif-1gamma branch controls lineage expansion, the Smad4 branch maintains the maturation stage that is initially repressed by a Tif-1gamma/Smad4-independent branch. Thus, these three different branches of TGF-beta signaling function in concert as complementary effectors, allowing TGF-beta to fine tune the iNKT cell differentiation program.
Published: 2009
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26. Stepwise development of MAIT cells in mouse and human

Author: Claire Soudais, Ivan C. Moura, Stéphane Cherif, Hélène Laude, Emmanuel Martin, Lucia Guerri, Cécile Toly, Livine Duban, Anne Devys, Florence Tilloy, Sylvain Latour, Virginie Premel, Gabriella Vera, Olivier Lantz, Emmanuel Treiner, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Inserm U925, équipe avenir, Développement normal et pathologique des lymphocytes et signalisation, Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang [Nantes], Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from INSERM, Action incitative (ACI) 'physiologie integrative,' Agence Nationale pour la Recherche (ANR), and Section Médicale de l'Institut Curie. The development of the 3C10 antibody was funded in part by Innate-Pharma (Marseille, France). OL is supported by la Ligue Contre le Cancer as an 'équipe labellisée.', Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Picardie Jules Verne ( UPJV ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Picardie Jules Verne ( UPJV ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Immunité et cancer (U932), and Autard, Delphine
Subjects: Adoptive cell transfer, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, MESH : Kruppel-Like Transcription Factors, MESH: T-Lymphocyte Subsets, MESH: Mice, Knockout, MESH: Histocompatibility Antigens Class I, Mice, 0302 clinical medicine, MESH : Child, T-Lymphocyte Subsets, MESH: Child, Cytotoxic T cell, Promyelocytic Leukemia Zinc Finger Protein, MESH: Animals, Biology (General), Child, Mice, Knockout, 0303 health sciences, B-Lymphocytes, MESH: Receptors, Antigen, T-Cell, alpha-beta, biology, MESH : Immunity, Mucosal, General Neuroscience, Natural killer T cell, Fetal Blood, MESH : Mice, Transgenic, Cell biology, MESH : Receptors, Antigen, T-Cell, alpha-beta, MESH : Histocompatibility Antigens Class I, MESH: Kruppel-Like Transcription Factors, Antibody, General Agricultural and Biological Sciences, Research Article, Genetically modified mouse, MESH: Mice, Transgenic, QH301-705.5, Immunology, Kruppel-Like Transcription Factors, Mice, Transgenic, Mucosal associated invariant T cell, Thymus Gland, Major histocompatibility complex, General Biochemistry, Genetics and Molecular Biology, MESH : B-Lymphocytes, Minor Histocompatibility Antigens, 03 medical and health sciences, MESH: B-Lymphocytes, MESH : Mice, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, MESH : Thymus Gland, MESH: Fetal Blood, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Immunity, Mucosal, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH : T-Lymphocytes, MESH : Fetal Blood, MESH: Humans, General Immunology and Microbiology, T-cell receptor, Histocompatibility Antigens Class I, MESH : Humans, MESH: Thymus Gland, MESH : Natural Killer T-Cells, MESH : T-Lymphocyte Subsets, Gastrointestinal Tract, MESH: T-Lymphocytes, MESH: Natural Killer T-Cells, MESH: Immunity, Mucosal, biology.protein, Natural Killer T-Cells, MESH : Mice, Knockout, MESH: Gastrointestinal Tract, MESH : Animals, MESH : Gastrointestinal Tract, 030215 immunology
Abstract: Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)α (iTCRα) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanVα7.2 antibody and MAIT cell-specific iTCRα and TCRβ transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRα and TCRβ transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%–4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and γδ T cells., Author Summary White blood cells, or lymphocytes, play an important role in defending the body from infection and disease. T lymphocytes come in many varieties with diverse functions. Mucosal-associated invariant T (MAIT) cells constitute a subset of unconventional T lymphocytes, characterized by their invariant T cell receptor (TCR)α chain and their requirement for the nonpolymorphic class Ib (MHC) molecule, MR1. MAIT cells are extremely abundant in human blood and mucosae. Contrary to mainstream T cells, their development requires B cells and commensal microbial flora. To shed light on the little-understood MAIT cells, we used new tools, including an antibody that we recently developed to detect human MAIT cells, and we were able to show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. We show that thymic selection is MR1 dependent but requires neither B cells nor the commensal flora, which are both necessary for the expansion in the periphery. In contrast with the other evolutionarily conserved invariant subset, the natural killer T (NKT) cells, we found that MAIT cells exit the thymus as “naïve” cells before becoming antigen-experienced memory cells and expanding in number to represent a significant 1%–4% of peripheral T cells in human blood. In mice, we found that MAIT cells remain naïve and do not expand substantially. We conclude that MAIT cell development follows a unique scheme, where, unlike NKT cells, MAIT cell selection and expansion are uncoupled events that are mediated by distinct cell types in different compartments., Mucosal-associated invariant T cells, the most abundant invariant T cell subset in humans, arise via a distinct developmental pathway that represents a hybrid of that seen for NKT and γδ T cells, two other unconventional T cell subsets.
Published: 2009
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27. Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia

Author: Laurence Legeai-Mallet, Nadia Messaddeq, Vincent Couloigner, Monique Elmaleh-Bergès, Stéphanie Pannier, Arnold Munnich, Raymond Romand, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Oto-Rhino-Laryngologie-Chirurgie Cervico-faciale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Service d'imagerie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This research was supported by EUROGROW and GIS-Maladies Rares. APHP/ CANAM was awarded to SP, Peney, Maité, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 )
Subjects: MESH : Tyrosine, Thanatophoric dysplasia, Labyrinth Diseases, Dwarfism, Hypochondroplasia, MESH: Tyrosine, Mice, 0302 clinical medicine, MESH: Animals, Achondroplasia, MESH: Heterozygote, 0303 health sciences, musculoskeletal system, MESH : Mice, Transgenic, Cell biology, Cochlea, medicine.anatomical_structure, MESH : Microscopy, Electron, Transmission, Chondrodysplasia, MESH: Microscopy, Electron, Transmission, Molecular Medicine, MESH : Mutation, musculoskeletal diseases, medicine.medical_specialty, MESH : Chondrodysplasia Punctata, MESH : Heterozygote, Chondrodysplasia Punctata, Heterozygote, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Enzyme Activation, MESH: Mutation, MESH: Receptor, Fibroblast Growth Factor, Type 3, MESH: Mice, Transgenic, Fgfr3, MESH : Receptor, Fibroblast Growth Factor, Type 3, Mice, Transgenic, Biology, MESH : Labyrinth Diseases, 03 medical and health sciences, Microscopy, Electron, Transmission, Internal medicine, MESH : Hearing Loss, MESH : Mice, medicine, otorhinolaryngologic diseases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Receptor, Fibroblast Growth Factor, Type 3, Inner ear, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Hearing Loss, MESH: Hearing Loss, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Labyrinth Diseases, Fibroblast growth factor receptor 3, medicine.disease, MESH : Disease Models, Animal, MESH: Chondrodysplasia Punctata, Pillar cell, Enzyme Activation, Disease Models, Animal, stomatognathic diseases, Endocrinology, Organ of Corti, Mutation, Tyrosine, MESH : Animals, sense organs, MESH: Disease Models, Animal, MESH : Enzyme Activation, 030217 neurology & neurosurgery
Abstract: Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of skeletal development and activating mutations in FGFR3 cause skeletal dysplasias, including hypochondroplasia, achondroplasia and thanatophoric dysplasia. The introduction of the Y367C mutation corresponding to the human Y373C thanatophoric dysplasia type I (TDI) mutation into the mouse genome, resulted in dwarfism with a skeletal phenotype remarkably similar to that of human chondrodysplasia. To investigate the role of the activating Fgfr3 Y367C mutation in auditory function, the middle and inner ear of the heterozygous mutant Fgfr3 Y367C/+ mice were examined. The mutant Fgfr3 Y367C/+ mice exhibit fully penetrant deafness with a significantly elevated auditory brainstem response threshold for all frequencies tested. The inner ear defect is mainly associated with an increased number of pillar cells or modified supporting cells in the organ of Corti. Hearing loss in the Fgfr3 Y367C/+ mouse model demonstrates the crucial role of Fgfr3 in the development of the inner ear and provides novel insight on the biological consequences of FGFR3 mutations in chondrodysplasia.
Published: 2009
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28. Mineralocorticoid Modulation of Cardiac Ryanodine Receptor Activity Is Associated With Downregulation of FK506-Binding Proteins

Author: Romain Perrier, Héctor H. Valdivia, Yannis Sainte-Marie, Ana María Gómez, Ćline Latouche, Frederic Jaisser, Spyros Zissimopoulos, Sylvain Richard, Xinsheng Zhu, Marie Christine Picot, Jean-Pierre Benitah, F. Anthony Lai, Emeline Perrier, Angélica Rueda, Roxane Schaub, Laetitia Pereira, Physiopathologie cardiovasculaire, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gènes et pression artérielle (INSERM U772), Collège de France (CdF (institution))-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wales Heart Research Institute, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Department of Physiology, University of Wisconsin Medical School, Département de l'Information Médicale, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, A05071FS/APV05030FSA, strep eurepe CT 2005 N°018802, CONTICA, Gomez, Ana Maria, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Gènes et pression artérielle ( Inserm U772 ), Collège de France ( CdF ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cardiff University School of Medicine, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Lapeyronie, and ANR : A05071FS/APV05030FSA,A05071FS/APV05030FSA
Subjects: Male, Patch-Clamp Techniques, MESH : Arrhythmias, Cardiac, MESH: Myocytes, Cardiac, 030204 cardiovascular system & hematology, MESH: Down-Regulation, MESH : Receptors, Mineralocorticoid, MESH: Ryanodine Receptor Calcium Release Channel, MESH : Down-Regulation, Mice, chemistry.chemical_compound, MESH : Calcium Signaling, 0302 clinical medicine, Mineralocorticoid receptor, MESH: Receptors, Mineralocorticoid, Myocytes, Cardiac, MESH: Animals, MESH : Patch-Clamp Techniques, Aldosterone, Cells, Cultured, MESH : Ryanodine Receptor Calcium Release Channel, Calcium signaling, 0303 health sciences, MESH : Rats, Ryanodine receptor, TOR Serine-Threonine Kinases, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Mice, Transgenic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Sarcoplasmic Reticulum, MESH: Arrhythmias, Cardiac, cardiovascular system, MESH: Sarcoplasmic Reticulum, MESH : Sarcoplasmic Reticulum, Cardiology and Cardiovascular Medicine, MESH: Cells, Cultured, RM, medicine.medical_specialty, MESH: Rats, medicine.drug_class, MESH: Mice, Transgenic, MESH : Male, MESH : Myocytes, Cardiac, Down-Regulation, Mice, Transgenic, MESH : Protein Kinases, MESH : Rats, Wistar, MESH : Tacrolimus Binding Proteins, MESH: Calcium Signaling, Tacrolimus Binding Proteins, 03 medical and health sciences, Downregulation and upregulation, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Mineralocorticoids, Physiology (medical), Internal medicine, MESH : Cells, Cultured, MESH : Mice, MESH: Patch-Clamp Techniques, medicine, Animals, Humans, Calcium Signaling, Patch clamp, Rats, Wistar, MESH: Protein Kinases, MESH: Mice, 030304 developmental biology, MESH: Tacrolimus Binding Proteins, Heart Failure, MESH: Humans, MESH : Aldosterone, business.industry, MESH : Humans, MESH: Aldosterone, Arrhythmias, Cardiac, Ryanodine Receptor Calcium Release Channel, MESH: Rats, Wistar, medicine.disease, R1, MESH : Mineralocorticoids, MESH: Male, Rats, Receptors, Mineralocorticoid, Endocrinology, chemistry, MESH: Mineralocorticoids, Mineralocorticoid, Heart failure, MESH: Heart Failure, MESH : Animals, MESH : Heart Failure, business, Protein Kinases
Abstract: Background— The mineralocorticoid pathway is involved in cardiac arrhythmias associated with heart failure through mechanisms that are incompletely understood. Defective regulation of the cardiac ryanodine receptor (RyR) is an important cause of the initiation of arrhythmias. Here, we examined whether the aldosterone pathway might modulate RyR function. Methods and Results— Using the whole-cell patch clamp method, we observed an increase in the occurrence of delayed afterdepolarizations during action potential recordings in isolated adult rat ventricular myocytes exposed for 48 hours to aldosterone 100 nmol/L, in freshly isolated myocytes from transgenic mice with human mineralocorticoid receptor expression in the heart, and in wild-type littermates treated with aldosterone. Sarcoplasmic reticulum Ca 2+ load and RyR expression were not altered; however, RyR activity, visualized in situ by confocal microscopy, was increased in all cells, as evidenced by an increased occurrence and redistribution to long-lasting and broader populations of spontaneous Ca 2+ sparks. These changes were associated with downregulation of FK506-binding proteins (FKBP12 and 12.6), regulatory proteins of the RyR macromolecular complex. Conclusions— We suggest that in addition to modulation of Ca 2+ influx, overstimulation of the cardiac mineralocorticoid pathway in the heart might be a major upstream factor for aberrant Ca 2+ release during diastole, which contributes to cardiac arrhythmia in heart failure.
Published: 2009
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29. ATP-binding cassette transporter A1 is significantly involved in the intestinal absorption of alpha- and gamma-tocopherol but not in that of retinyl palmitate in mice

Author: Doriane Trompier, Emmanuelle Reboul, Alexis Klein, Jean-François Landrier, Giovanna Chimini, Myriam Moussa, Patrick Borel, Nutrition humaine et lipides : Biodisponibilité, métabolisme et régulation, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique (INRA)-Université de Provence - Aix-Marseille 1-IFR125-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Departement of Mathematics, University of California [Irvine] (UCI), University of California-University of California, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut de physiopathologie humaine de Marseille (IPHM), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique ( INRA ) -Université de Provence - Aix-Marseille 1-IFR125-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan - Institut Fédératif de Biologie (IFB), University of California [Irvine] ( UCI ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), and Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Retinyl Esters, 030309 nutrition & dietetics, medicine.medical_treatment, alpha-Tocopherol, Medicine (miscellaneous), MESH : Nutritional Status, Intestinal absorption, Transgenic, chemistry.chemical_compound, Mice, MESH: Vitamin E, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Vitamin E, MESH: Animals, Tocopherol, Vitamin A, Chromatography, High Pressure Liquid, MESH: Vitamin A, 0303 health sciences, Chromatography, Nutrition and Dietetics, Retinol, MESH: Nutritional Status, MESH : Mice, Transgenic, MESH : gamma-Tocopherol, MESH: gamma-Tocopherol, Cholesterol, MESH: alpha-Tocopherol, Mice, Inbred DBA, MESH : alpha-Tocopherol, High Pressure Liquid, MESH : Cholesterol, HDL, MESH: ATP-Binding Cassette Transporters, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), MESH: Caco-2 Cells, Diterpenes, MESH: Cholesterol, HDL, ATP Binding Cassette Transporter 1, Vitamin, medicine.medical_specialty, HDL, MESH : Mice, Inbred DBA, Active, MESH: Mice, Transgenic, MESH: Intestinal Absorption, gamma-Tocopherol, Biological Transport, Active, Nutritional Status, Mice, Transgenic, MESH : Vitamin A, MESH : Chromatography, High Pressure Liquid, 03 medical and health sciences, MESH : Vitamin E, Internal medicine, Retinyl palmitate, MESH : Mice, medicine, Animals, Humans, Inbred DBA, MESH : ATP-Binding Cassette Transporters, MESH : Biological Transport, Active, MESH: Chromatography, High Pressure Liquid, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH: Mice, Inbred DBA, MESH : Humans, Cholesterol, HDL, MESH : Intestinal Absorption, MESH : Caco-2 Cells, Biological Transport, Endocrinology, chemistry, Intestinal Absorption, MESH: Biological Transport, Active, ATP-Binding Cassette Transporters, MESH : Animals, Caco-2 Cells
Abstract: International audience; BACKGROUND: It has long been assumed that newly absorbed vitamin A and E enter the body only via enterocyte-produced chylomicrons. However, recent results in cell cultures have shown that a fraction of alpha-tocopherol is secreted with intestinal HDL. OBJECTIVES: The aims of this study were to identify this transporter and to assess whether it is significantly implicated in the in vivo intestinal absorption of the 2 main dietary forms of vitamin E (ie, alpha- and gamma-tocopherol) and in that of retinyl palmitate (vitamin A). DESIGN: Having performed preliminary experiments in the Caco-2 cell model, we compared fasting and postprandial plasma concentrations of vitamins A and E in mice deficient in ATP-binding cassette A1 (ABCA1) transporter and in wild-type mice. RESULTS: A substantial efflux of alpha- and gamma-tocopherol, but not of retinyl esters, was induced by the presence of apolipoprotein A-I at the basolateral side of Caco-2 monolayers. The efflux of alpha- and gamma-tocopherol was also impaired by glyburide and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. The postprandial response of plasma gamma-tocopherol was 4-fold lower in ABCA1(-/-) mice (P = 0.025) than in wild-type mice, whereas no significant difference was observed for retinyl esters. Fasting plasma alpha-tocopherol, but not vitamin A, concentrations were lower in mice bearing the genetic deletion. CONCLUSIONS: ABCA1 is the transporter responsible for the in vivo secretion of alpha- and gamma-tocopherol with intestinal HDL, and this pathway is significantly implicated in the intestinal absorption and plasma status of vitamin E but not of vitamin A.
Published: 2009
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30. Tumor Suppressor Schwannomin/Merlin Is Critical for the Organization of Schwann Cell Contacts in Peripheral Nerves

Author: Carmen Cifuentes-Diaz, Jean-Antoine Girault, Michèle Carnaud, Natalia Denisenko, Fabrice Chareyre, Marco Giovannini, Michiko Niwa-Kawakita, Laurence Goutebroze, Evelyne Benoit, Theano Irinopoulou, Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurobiologie Alfred Fessard (INAF), Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Neurobiologie Alfred Fessard ( INAF ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de neurobiologie cellulaire et moléculaire ( NBCM ), Genomique Fonctionnelle des Tumeurs Solides, and Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Cellular differentiation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell Communication, MESH : Gene Deletion, Schwann cell proliferation, Mice, 0302 clinical medicine, Compact myelin, MESH : Cell Proliferation, MESH: Animals, Neurofibromatosis type 2, ComputingMilieux_MISCELLANEOUS, MESH : Neurofibromin 2, Neurofibromin 2, 0303 health sciences, MESH : Tumor Suppressor Proteins, General Neuroscience, MESH : Peripheral Nerves, MESH: Neurofibromin 2, Articles, MESH : Mice, Transgenic, Cell biology, medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Cell Communication, Tumor suppressor gene, MESH: Mice, Transgenic, MESH : Schwann Cells, Schwann cell, Mice, Transgenic, Biology, 03 medical and health sciences, MESH: Cell Proliferation, MESH : Mice, MESH: Cell Communication, medicine, Animals, Humans, MESH: Tumor Suppressor Proteins, Peripheral Nerves, MESH: Mice, Cell Proliferation, 030304 developmental biology, MESH: Humans, Tumor Suppressor Proteins, MESH : Humans, medicine.disease, MESH: Peripheral Nerves, Merlin (protein), nervous system, Cytoplasm, MESH: Gene Deletion, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Schwann Cells, MESH : Animals, MESH: Schwann Cells, Neuroscience, Gene Deletion, 030217 neurology & neurosurgery
Abstract: Schwannomin/merlin is the product of a tumor suppressor gene mutated in neurofibromatosis type 2 (NF2). Although the consequences of NF2 mutations on Schwann cell proliferation are well established, the physiological role of schwannomin in differentiated cells is not known. To unravel this role, we studied peripheral nerves in mice overexpressing in Schwann cells schwannomin with a deletion occurring in NF2 patients (P0–SCH–Δ39–121) or a C-terminal deletion. The myelin sheath and nodes of Ranvier were essentially preserved in both lines. In contrast, the ultrastructural and molecular organization of contacts between Schwann cells and axons in paranodal and juxtaparanodal regions were altered, with irregular juxtaposition of normal and abnormal areas of contact. Similar but more severe alterations were observed in mice with conditional deletion of theNf2gene in Schwann cells. The number of Schmidt–Lanterman incisures, which are cytoplasmic channels interrupting the compact myelin and characterized by distinct autotypic contacts, was increased in the three mutant lines. P0–SCH–Δ39–121 and conditionally deleted mice displayed exuberant wrapping of nonmyelinated fibers and short internodes, an abnormality possibly related to altered control of Schwann cell proliferation. In support of this hypothesis, Schwann cell number was increased along fibers before myelination in P0–SCH–Δ39–121 mice but not in those with C-terminal deletion. Schwann cell numbers were also more numerous in mice with conditional deletion. Thus, schwannomin plays an important role in the control of Schwann cell number and is necessary for the correct organization and regulation of axoglial heterotypic and glio-glial autotypic contacts.
Published: 2008
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31. Evidence of a dosage effect and a physiological endplate acetylcholinesterase deficiency in the first mouse models mimicking Schwartz-Jampel syndrome neuromyotonia

Author: Morgane Stum, Arnaud Ferry, Frédédrique Rene, Christophe Marcel, Andoni Echaniz-Laguna, Véronique Bernard, Claire-Sophie Davoine, Bertrand Fontaine, Eric Krejci, Sophie Nicole, Alban Vignaud, Marie Bangratz, Emmanuelle Girard, Jordi Molgó, Marc Herbin, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), Biologie des Jonctions Neuromusculaires Normales et Pathologiques (U686), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mécanismes adaptatifs : des organismes aux communautés (MAOAC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Groupe Myologie, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de signalisation moléculaire et neurodégénerescence, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Neurologie, Hôpital Civil de Strasbourg, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Muséum national d'Histoire naturelle (MNHN)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire de neurobiologie cellulaire et moléculaire ( NBCM ), Centre National de la Recherche Scientifique ( CNRS ), Institut de Neurobiologie Alfred Fessard ( INAF ), Biologie des Jonctions Neuromusculaires Normales et Pathologiques ( U686 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Mécanismes adaptatifs : des organismes aux communautés ( MAOAC ), Muséum National d'Histoire Naturelle ( MNHN ) -Collège de France ( CdF ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]
Subjects: Male, Neuromyotonia, MESH: Mice, Mutant Strains, MESH: Muscle Contraction, Gene Dosage, medicine.disease_cause, MESH: Gene Dosage, MESH: Motor Endplate, chemistry.chemical_compound, Mice, 0302 clinical medicine, Missense mutation, MESH : Female, MESH : Gene Dosage, MESH: Animals, Genetics (clinical), 0303 health sciences, Mutation, biology, General Medicine, Acetylcholinesterase, MESH : Mice, Transgenic, MESH : Phenotype, medicine.anatomical_structure, Phenotype, MESH : Electromyography, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Heparan Sulfate Proteoglycans, Muscle Contraction, medicine.medical_specialty, MESH : Isaacs Syndrome, MESH: Mice, Transgenic, MESH : Male, Schwartz–Jampel syndrome, Mutation, Missense, Mice, Transgenic, MESH : Mice, Inbred C57BL, Perlecan, Osteochondrodysplasias, MESH: Phenotype, Motor Endplate, Neuromuscular junction, MESH : Acetylcholinesterase, MESH: Electromyography, 03 medical and health sciences, In vivo, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Mice, Genetics, medicine, Animals, Humans, MESH: Isaacs Syndrome, Molecular Biology, MESH: Mice, Alleles, 030304 developmental biology, MESH : Osteochondrodysplasias, MESH: Mutation, Missense, MESH: Humans, Electromyography, MESH: Alleles, MESH : Humans, MESH : Motor Endplate, MESH: Acetylcholinesterase, medicine.disease, MESH: Osteochondrodysplasias, MESH : Disease Models, Animal, Mice, Mutant Strains, MESH: Male, MESH : Mice, Mutant Strains, Mice, Inbred C57BL, Disease Models, Animal, stomatognathic diseases, Endocrinology, chemistry, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], biology.protein, MESH: Heparan Sulfate Proteoglycans, MESH : Muscle Contraction, MESH : Animals, Isaacs Syndrome, MESH: Disease Models, Animal, MESH : Alleles, MESH: Female, MESH : Mutation, Missense, 030217 neurology & neurosurgery, Heparan Sulfate Proteoglycans
Abstract: International audience; Schwartz-Jampel syndrome (SJS) is a recessive neuromyotonia with chondrodysplasia. It results from hypomorphic mutations of the gene encoding perlecan, leading to a decrease in the levels of this heparan sulphate proteoglycan in basement membranes (BMs). It has been suggested that SJS neuromyotonia may result from endplate acetylcholinesterase (AChE) deficiency, but this hypothesis has never been investigated in vivo due to the lack of an animal model for neuromyotonia. We used homologous recombination to generate a knock-in mouse strain with one missense substitution, corresponding to a human familial SJS mutation (p.C1532Y), in the perlecan gene. We derived two lines, one with the p.C1532Y substitution alone and one with p.C1532Y and the selectable marker Neo, to down-regulate perlecan gene activity and to test for a dosage effect of perlecan in mammals. These two lines mimicked SJS neuromyotonia with spontaneous activity on electromyogramm (EMG). An inverse correlation between disease severity and perlecan secretion in the BMs was observed at the macroscopic and microscopic levels, consistent with a dosage effect. Endplate AChE levels were low in both lines, due to synaptic perlecan deficiency rather than major myofibre or neuromuscular junction disorganization. Studies of muscle contractile properties showed muscle fatigability at low frequencies of nerve stimulation and suggested that partial endplate AChE deficiency might contribute to SJS muscle stiffness by potentiating muscle force. However, physiological endplate AChE deficiency was not associated with spontaneous activity at rest on EMG in the diaphragm, suggesting that additional changes are required to generate such activity characteristic of SJS.
Published: 2008
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32. Cardiomyocyte overexpression of neuronal nitric oxide synthase delays transition toward heart failure in response to pressure overload by preserving calcium cycling

Author: Estelle Robidel, Bernd Mayer, Christophe Heymes, Laurent Vinet, Emilie Vaudin, Ana María Gómez, María Fernández-Velasco, Xavier Loyer, Paul Milliez, Dominique Charue, Jean-Jacques Mercadier, Ajay M. Shah, Frederic Jaisser, Sylvain Richard, Isabelle Marty, Yannis Sainte-Marie, Jane-Lise Samuel, Jean-Pierre Benitah, Peter Vangheluwe, Wei Zhang, Centre de Recherche Cardiovasculaire de Lariboisiere, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie cardiovasculaire, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Ca-transport ATPases, The James Black Centre, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Gènes et pression artérielle (INSERM U772), Collège de France (CdF (institution))-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular Division, King‘s College London, Roux-Buisson, Nathalie, Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Grenoble Institut des Neurosciences ( GIN ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Gènes et pression artérielle ( Inserm U772 ), and Collège de France ( CdF ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH: Signal Transduction, MESH: Myocardial Contraction, heart failure, MESH: Myocytes, Cardiac, Blood Pressure, MESH: Nitric Oxide Synthase Type I, Cell Separation, Nitric Oxide Synthase Type I, 030204 cardiovascular system & hematology, Ventricular Function, Left, MESH: Ventricular Function, Left, Muscle hypertrophy, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Nitric Oxide Synthase Type I, Myocyte, Myocytes, Cardiac, MESH: Animals, MESH : Myocardial Contraction, Aorta, remodeling, 0303 health sciences, biology, Reverse Transcriptase Polymerase Chain Reaction, nitric oxide synthase, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Aorta, MESH: Blood Pressure, MESH : Mice, Transgenic, Phospholamban, Nitric oxide synthase, MESH: Calcium, Disease Progression, MESH: Disease Progression, Cardiology and Cardiovascular Medicine, hypertrophy, Signal Transduction, MESH : Ventricular Function, Left, medicine.medical_specialty, MESH: Enzyme Activation, MESH: Mice, Transgenic, MESH : Myocytes, Cardiac, Concentric hypertrophy, Mice, Transgenic, MESH: Cell Separation, Contractility, 03 medical and health sciences, Physiology (medical), Internal medicine, MESH : Mice, medicine, MESH : Blood Pressure, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Calcium, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, Pressure overload, MESH : Signal Transduction, calcium, MESH: Humans, business.industry, MESH : Humans, MESH : Aorta, MESH : Disease Progression, medicine.disease, MESH : Disease Models, Animal, Myocardial Contraction, Enzyme Activation, Disease Models, Animal, Endocrinology, Heart failure, MESH : Cell Separation, MESH: Heart Failure, biology.protein, MESH : Animals, MESH: Disease Models, Animal, business, MESH : Enzyme Activation, MESH : Heart Failure
Abstract: Background— Defects in cardiomyocyte Ca 2+ cycling are a signature feature of heart failure (HF) that occurs in response to sustained hemodynamic overload, and they largely account for contractile dysfunction. Neuronal nitric oxide synthase (NOS1) influences myocyte excitation-contraction coupling through modulation of Ca 2+ cycling, but the potential relevance of this in HF is unknown. Methods and Results— We generated a transgenic mouse with conditional, cardiomyocyte-specific NOS1 overexpression (double-transgenic [DT]) and studied cardiac remodeling, myocardial Ca 2+ handling, and contractility in DT and control mice subjected to transverse aortic constriction (TAC). After TAC, control mice developed eccentric hypertrophy with evolution toward HF as revealed by a significantly reduced fractional shortening. In contrast, DT mice developed a greater increase in wall thickness ( P P P 2+ transients, and sarcoplasmic reticulum Ca 2+ load ( P Conclusions— Cardiomyocyte NOS1 may be a useful target against cardiac deterioration during chronic pressure-overload–induced HF through modulation of calcium cycling.
Published: 2008
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33. Prolactin signaling through the short form of its receptor represses forkhead transcription factor FOXO3 and its target gene galt causing a severe ovarian defect

Author: Diane Rebourcet, Sangeeta Y. Devi, Nadine Binart, Carlos Stocco, Nancy D. Leslie, Geula Gibori, Julia Halperin, Aurora Shehu, Jamie Le, Terry G. Unterman, Shai E. Elizur, Department of Physiology and Biophysics, College of Medicine of Chicago, Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Medecine, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Cincinnati Children's Hospital Medical Center, Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and University of Illinois at Chicago ( UIC )
Subjects: MESH: Signal Transduction, endocrine system diseases, Transcription, Genetic, MESH : Genotype, Electrophoretic Mobility Shift Assay, MESH : Blotting, Western, MESH: Mice, Knockout, MESH: Genotype, Mice, Endocrinology, Ovarian Follicle, MESH : Prolactin, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Female, MESH: Animals, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Receptor, Mice, Knockout, Regulation of gene expression, MESH : Gene Expression Regulation, Reverse Transcriptase Polymerase Chain Reaction, Forkhead Box Protein O3, MESH : Reverse Transcriptase Polymerase Chain Reaction, Forkhead Transcription Factors, General Medicine, MESH: Gene Expression Regulation, MESH : Mice, Transgenic, Premature ovarian failure, Cell biology, MESH : Forkhead Transcription Factors, medicine.anatomical_structure, MESH : Electrophoretic Mobility Shift Assay, FOXO3, Female, Signal transduction, Signal Transduction, MESH: Ovary, medicine.medical_specialty, endocrine system, MESH: Cell Line, Tumor, Genotype, Receptors, Prolactin, MESH: Mice, Transgenic, MESH : Ovarian Follicle, Blotting, Western, MESH: Prolactin, Mice, Transgenic, Ovary, Biology, Article, MESH: Receptors, Prolactin, MESH: Forkhead Transcription Factors, Cell Line, Tumor, Internal medicine, MESH : Mice, medicine, Animals, Humans, UTP-Hexose-1-Phosphate Uridylyltransferase, MESH: Blotting, Western, Ovarian follicle, Molecular Biology, Transcription factor, MESH: Mice, MESH : Receptors, Prolactin, MESH : Ovary, MESH : Signal Transduction, MESH: Humans, MESH: UTP-Hexose-1-Phosphate Uridylyltransferase, MESH : Cell Line, Tumor, MESH: Transcription, Genetic, MESH : Humans, MESH : Transcription, Genetic, MESH : UTP-Hexose-1-Phosphate Uridylyltransferase, medicine.disease, MESH: Ovarian Follicle, Prolactin, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Electrophoretic Mobility Shift Assay, MESH : Mice, Knockout, MESH : Animals, MESH: Female
Abstract: Prolactin (PRL) is a hormone with over 300 biological activities. Although the signaling pathway downstream of the long form of its receptor (RL) has been well characterized, little is known about PRL actions upon activation of the short form (RS). Here, we show that mice expressing only RS exhibit an ovarian phenotype of accelerated follicular recruitment followed by massive follicular death leading to premature ovarian failure. Consequently, RS-expressing ovaries of young adults are depleted of functional follicles and formed mostly by interstitium. We also show that activation of RS represses the expression of the transcription factor Forkhead box O3 (FOXO3) and that of the enzyme galactose-1-phosphate uridyltransferase (Galt), two proteins known to be essential for normal follicular development. Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death. Coexpression of RL with RS prevents PRL inhibition of Galt, and the ovarian defect is no longer seen in RS transgenic mice that coexpress RL, suggesting that RL prevents RS-induced ovarian impairment. In summary, we show that PRL signals through RS and causes, in the absence of RL, a severe ovarian pathology by repressing the expression of FOXO3 and that of its target gene Galt. We also provide evidence of a link between the premature ovarian failure seen in mice expressing RS and in mice with FOXO3 gene deletion as well as in human with Galt mutation.
Published: 2008
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34. Developmental regulation of the membrane properties of central vestibular neurons by sensory vestibular information in the mouse

Author: Eugene, D., Deforges, S., Guimont, F., Vidoux, E., Vidal, P.P., Moore, L.E., Vibert, Nicolas, Laboratoire de Neurobiologie des Réseaux Sensorimoteurs (LNRS), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5), Department of Biomedical Engineering [Boston], Boston University [Boston] (BU), Centre de Recherches sur la Cognition et l'Apprentissage (CeRCA), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurobiologie des Réseaux Sensorimoteurs ( LNRS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ), Boston University [Boston] ( BU ), Centre de Recherches sur la Cognition et l'Apprentissage ( CeRCA ), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Université de Poitiers, and Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH : RNA, Messenger, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Head Movements, MESH: Calcium-Binding Proteins, MESH : Behavior, Animal, MESH: Chelating Agents, MESH : Parvalbumins, MESH : Calcium-Binding Proteins, MESH: Behavior, Animal, MESH: Gene Expression Regulation, Developmental, MESH : Membrane Potentials, MESH: Animals, MESH: Nerve Tissue Proteins, MESH : Potassium Channels, Voltage-Gated, MESH : Patch-Clamp Techniques, MESH : Nerve Tissue Proteins, MESH : Organ Culture Techniques, MESH : Mice, Inbred Strains, MESH: Electric Capacitance, MESH : Egtazic Acid, MESH : Calcium-Binding Protein, Vitamin D-Dependent, MESH : Mice, Transgenic, MESH : Phenotype, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SCCO.PSYC]Cognitive science/Psychology, MESH: Vestibular Nuclei, MESH: Mice, Transgenic, MESH: Egtazic Acid, MESH: Phenotype, MESH: Mice, Inbred Strains, MESH : Electric Capacitance, MESH: Parvalbumins, MESH : Mice, MESH: Patch-Clamp Techniques, otorhinolaryngologic diseases, MESH: Membrane Potentials, MESH : Chelating Agents, MESH: Mice, MESH: RNA, Messenger, MESH: Age Factors, MESH: Calcium-Binding Protein, Vitamin D-Dependent, MESH : Critical Period (Psychology), MESH: Organ Culture Techniques, MESH: Hair Cells, Vestibular, MESH: Critical Period (Psychology), MESH : Head Movements, nervous system, MESH : Hair Cells, Vestibular, MESH : Age Factors, MESH : Animals, MESH : Gene Expression Regulation, Developmental, sense organs, MESH : Vestibular Nuclei, MESH: Potassium Channels, Voltage-Gated
Abstract: International audience; The effect of the lack of vestibular input on the membrane properties of central vestibular neurons was studied by using a strain of transgenic, vestibular-deficient mutant KCNE1(-/-) mice where the hair cells of the inner ear degenerate just after birth. Despite the absence of sensory vestibular input, their central vestibular pathways are intact. Juvenile and adult homozygous mutant have a normal resting posture, but show a constant head bobbing behaviour and display the shaker/waltzer phenotype characterized by rapid bilateral circling during locomotion. In juvenile mice, the KCNE1 mutation was associated with a strong decrease in the expression of the calcium-binding proteins calbindin, calretinin and parvalbumin within the medial vestibular nucleus (MVN) and important modifications of the membrane properties of MVN neurons. In adult mice, however, there was almost no difference between the membrane properties of MVN neurons of homozygous and control or heterozygous mutant mice, which have normal inner ear hair cells and show no behavioural symptoms. The expression levels of calbindin and calretinin were lower in adult homozygous mutant animals, but the amount of calcium-binding proteins expressed in the MVN was much greater than in juvenile mice. These data demonstrate that suppression of sensory vestibular inputs during a 'sensitive period' around birth can generate the circling/waltzing behaviour, but that this behaviour is not due to persistent abnormalities of the membrane properties of central vestibular neurons. Altogether, maturation of the membrane properties of central vestibular neurons is delayed, but not impaired by the absence of sensory vestibular information.
Published: 2007
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35. Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination

Author: Pierre Charneau, Christelle Olivier-Martin, Jean-Pierre de Villartay, Gwenaël Le Guyader, Paola Rivera-Munoz, Vincent Abramowski, Pauline Soulas-Sprauel, Cécile Goujet-Zalc, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Transgenèse et archivage d'animaux modèles (TAAM), Centre National de la Recherche Scientifique (CNRS), Virologie moléculaire et Vectorologie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Transgenèse et archivage d'animaux modèles ( TAAM ), Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: DNA Repair, medicine.disease_cause, MESH: Mice, Knockout, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH : DNA Repair, Immunology and Allergy, MESH: Animals, MESH: Lentivirus, Mice, Knockout, MESH: DNA Repair, B-Lymphocytes, 0303 health sciences, Mutation, Articles, DNA repair protein XRCC4, MESH : Mice, Transgenic, DNA-Binding Proteins, Non-homologous end joining, MESH : Lentivirus, 030220 oncology & carcinogenesis, MESH: Immunoglobulin Class Switching, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA-Binding Proteins, MESH : Mutation, MESH: Mutation, DNA repair, MESH: Mice, Transgenic, Immunology, Mice, Transgenic, chemical and pharmacologic phenomena, Biology, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Article, Immunoglobulin Class Switch Recombination, MESH : B-Lymphocytes, 03 medical and health sciences, MESH: B-Lymphocytes, MESH : Mice, medicine, Animals, MESH : Immunoglobulin Class Switching, MESH: Mice, 030304 developmental biology, Lentivirus, DNA Repair Pathway, Immunoglobulin Class Switching, Molecular biology, chemistry, Immunoglobulin class switching, MESH : Genes, Lethal, MESH : Mice, Knockout, Genes, Lethal, MESH : Animals, MESH: Genes, Lethal, DNA, MESH: DNA-Binding Proteins
Abstract: International audience; V(D)J recombination and immunoglobulin class switch recombination (CSR) are two somatic rearrangement mechanisms that proceed through the introduction of double-strand breaks (DSBs) in DNA. Although the DNA repair factor XRCC4 is essential for the resolution of DNA DSB during V(D)J recombination, its role in CSR has not been established. To bypass the embryonic lethality of XRCC4 deletion in mice, we developed a conditional XRCC4 knockout (KO) using LoxP-flanked XRCC4 cDNA lentiviral transgenesis. B lymphocyte restricted deletion of XRCC4 in these mice lead to an average two-fold reduction in CSR in vivo and in vitro. Our results connect XRCC4 and the nonhomologous end joining DNA repair pathway to CSR while reflecting the possible use of an alternative pathway in the repair of CSR DSB in the absence of XRCC4. In addition, this new conditional KO approach should be useful in studying other lethal mutations in mice.
Published: 2007
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36. Early electrophysiological abnormalities in lumbar motoneurons in a transgenic mouse model of amyotrophic lateral sclerosis

Author: Jacques Durand, Cyril Bories, Julien Amendola, Boris Lamotte d'Incamps, Plasticité et physio-pathologie de la motricité (P3M) (PPPMP), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Neurophysique et physiologie du système moteur (NPSM), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université de la Méditerranée - Aix-Marseille 2 - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)
Subjects: Patch-Clamp Techniques, MESH: Strychnine, MESH : Electric Stimulation, Stimulation, Transgenic Model, Membrane Potentials, MESH: Spinal Cord, Mice, 0302 clinical medicine, Superoxide Dismutase-1, MESH : Glycine Agents, MESH : Membrane Potentials, MESH: Animals, Amyotrophic lateral sclerosis, MESH : Patch-Clamp Techniques, MESH: Amyotrophic Lateral Sclerosis, MESH: Superoxide Dismutase, Motor Neurons, 0303 health sciences, biology, General Neuroscience, MESH: Electric Stimulation, Glycine Agents, Strychnine, MESH : Mice, Transgenic, MESH : Lumbosacral Region, medicine.anatomical_structure, Spinal Cord, MESH : Strychnine, MESH : Dose-Response Relationship, Radiation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Motor Neurons, Genetically modified mouse, medicine.medical_specialty, MESH : Motor Neurons, MESH: Mice, Transgenic, SOD1, MESH: Glycine Agents, Mice, Transgenic, MESH : Mice, Inbred C57BL, MESH: Lumbosacral Region, Superoxide dismutase, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Amyotrophic Lateral Sclerosis, MESH : Mice, MESH: Patch-Clamp Techniques, MESH: Dose-Response Relationship, Radiation, medicine, Animals, MESH: Membrane Potentials, MESH : Superoxide Dismutase, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, 030304 developmental biology, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Lumbosacral Region, Dose-Response Relationship, Radiation, MESH : Spinal Cord, medicine.disease, Spinal cord, MESH : Disease Models, Animal, Electric Stimulation, Mice, Inbred C57BL, Electrophysiology, Disease Models, Animal, Endocrinology, nervous system, biology.protein, MESH : Animals, MESH: Disease Models, Animal, Neuroscience, 030217 neurology & neurosurgery
Abstract: Amyotrophic lateral sclerosis is a lethal, adult-onset disease characterized by progressive degeneration of motoneurons. Recent data have suggested that the disease could be linked to abnormal development of the motor nervous system. Therefore, we investigated the electrical properties of lumbar motoneurons in an in-vitro neonatal spinal cord preparation isolated from SOD1(G85R) mice, which is a transgenic model of amyotrophic lateral sclerosis. The study was performed on young animals at the beginning of their second week, between postnatal days 6 and 10. Measurements of resting membrane potential and action potential characteristics of motoneurons were similar in wild-type and SOD1(G85R) mice. However, the input resistance of motoneurons from transgenic mice was significantly lower than that of wild-type animals, whereas their membrane capacitance was increased, strongly suggesting larger SOD1(G85R) motoneurons. Furthermore, the slope of the frequency-intensity curve was steeper in motoneurons from wild-type pups. Interestingly, the input resistance as well as the slope of the frequency-intensity curves of other spinal neurons did not show such differences. Finally, the amplitude of dorsal root-evoked potentials following high-intensity stimulation was significantly smaller in SOD1(G85R) motoneurons. The superoxide dismutase 1 mutation thus induces specific alterations of the functional properties of motoneurons early in development.
Published: 2007
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37. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127

Author: Benedita Rocha, Ana Cumano, Sophie Ezine, Erwan Corcuff, Lars Rogge, Marcos E. García-Ojeda, Odile Richard-Le Goff, Christian A. J. Vosshenrich, Sandrine I. Samson-Villeger, Delphine Guy-Grand, James P. Di Santo, Valérie Pasqualetto, Laurence Enault, Cytokines et Développement Lymphoïde, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Differenciation Thymique et Physiologie des Lymphocytes T (U591), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Développement des Lymphocytes, Immunorégulation, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Differenciation Thymique et Physiologie des Lymphocytes T ( U591 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS )
Subjects: Cytotoxicity, Immunologic, MESH: Signal Transduction, MESH : GATA3 Transcription Factor, MESH : Cytokines, MESH : Cytotoxicity, Immunologic, MESH : Interleukin-7 Receptor alpha Subunit, Interleukin 21, Mice, 0302 clinical medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, MESH: Animals, 0303 health sciences, MESH: Cytokines, MESH : Lymphocyte Subsets, MESH : Mice, Nude, Interleukin, virus diseases, Cell Differentiation, hemic and immune systems, Natural killer T cell, MESH : Mice, Transgenic, Cell biology, Killer Cells, Natural, MESH : Immunophenotyping, Interleukin 12, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : Killer Cells, Natural, MESH : Cell Differentiation, Signal Transduction, MESH : Interleukin-7, MESH: Cell Differentiation, MESH: Killer Cells, Natural, MESH: Immunophenotyping, MESH: Mice, Transgenic, Immunology, MESH: Lymphocyte Subsets, Mice, Nude, Mice, Transgenic, chemical and pharmacologic phenomena, MESH : Mice, Inbred C57BL, GATA3 Transcription Factor, Thymus Gland, Biology, CD16, Immunophenotyping, Interleukin-7 Receptor alpha Subunit, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH : Mice, MESH: GATA3 Transcription Factor, MESH: Mice, Nude, Animals, Humans, MESH : Thymus Gland, MESH: Cytotoxicity, Immunologic, MESH: Mice, 030304 developmental biology, MESH : Signal Transduction, Lymphokine-activated killer cell, MESH: Humans, Cell growth, Interleukin-7, MESH : Humans, MESH: Interleukin-7 Receptor alpha Subunit, MESH: Thymus Gland, Lymphocyte Subsets, MESH: Interleukin-7, Mice, Inbred C57BL, Myeloid-derived Suppressor Cell, MESH : Animals, 030215 immunology
Abstract: International audience; Natural killer (NK) cell development is thought to occur in the bone marrow. Here we identify the transcription factor GATA-3 and CD127 (IL-7R alpha) as molecular markers of a pathway of mouse NK cell development that originates in the thymus. Thymus-derived CD127+ NK cells repopulated peripheral lymphoid organs, and their homeostasis was strictly dependent on GATA-3 and interleukin 7. The CD127+ NK cells had a distinct phenotype (CD11b(lo) CD16- CD69(hi) Ly49(lo)) and unusual functional attributes, including reduced cytotoxicity but considerable cytokine production. Those characteristics are reminiscent of human CD56(hi) CD16- NK cells, which we found expressed CD127 and had more GATA-3 expression than human CD56+ CD16+ NK cells. We propose that bone marrow and thymic NK cell pathways generate distinct mouse NK cells with properties similar to those of the two human CD56 NK cell subsets.
Published: 2006
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38. Natural killer cell behavior in lymph nodes revealed by static and real-time imaging

Author: Béatrice Breart, Hai Qi, Veronique M. Braud, Marc Bajénoff, Ronald N. Germain, Alex Yee-Chen Huang, Nicolas Glaichenhaus, Julie Cazareth, Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), National Institutes of Health, Bethesda ( NIH ), National Institutes of Health ( NIH ), Université Côte d'Azur ( UCA ), Immunologie des Maladies Infectieuses Allergiques et Autoimmunes, Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health, Bethesda (NIH), National Institutes of Health [Bethesda] (NIH), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: CD4-Positive T-Lymphocytes, MESH: Signal Transduction, MESH: Inflammation, Cellular differentiation, MESH : Immunohistochemistry, MESH: Lymph Nodes, MESH : Leishmaniasis, Cutaneous, Lymphocyte Activation, Mice, Interleukin 21, 0302 clinical medicine, MESH: Leishmania major, Immunology and Allergy, Interferon gamma, MESH: Animals, MESH : Lymph Nodes, Leishmania major, Mice, Inbred BALB C, 0303 health sciences, MESH: CD4-Positive T-Lymphocytes, Cell Differentiation, MESH : Interferon Type II, Articles, Acquired immune system, Immunohistochemistry, MESH : Mice, Transgenic, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, MESH : CD4-Positive T-Lymphocytes, MESH : Killer Cells, Natural, MESH : Cell Differentiation, Intravital microscopy, Signal Transduction, medicine.drug, MESH: Cell Differentiation, MESH: Killer Cells, Natural, MESH: Mice, Transgenic, MESH: Interferon Type II, T cell, Immunology, MESH: Mice, Inbred BALB C, Leishmaniasis, Cutaneous, Mice, Transgenic, Biology, Article, Natural killer cell, MESH : Leishmania major, Interferon-gamma, 03 medical and health sciences, MESH : Microscopy, Fluorescence, Multiphoton, MESH : Mice, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Lymphocyte Activation, MESH: Mice, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Lymphocyte Activation, MESH : Mice, Inbred BALB C, 030304 developmental biology, Inflammation, MESH : Signal Transduction, MESH: Humans, MESH : Inflammation, MESH : Humans, MESH: Immunohistochemistry, Dendritic cell, Cell Biology, MESH: Leishmaniasis, Cutaneous, Microscopy, Fluorescence, Multiphoton, MESH: Microscopy, Fluorescence, Multiphoton, Lymph Nodes, MESH : Animals, 030215 immunology
Abstract: Natural killer (NK) cells promote dendritic cell (DC) maturation and influence T cell differentiation in vitro. To better understand the nature of the putative interactions among these cells in vivo during the early phases of an adaptive immune response, we have used immunohistochemical analysis and dynamic intravital imaging to study NK cell localization and behavior in lymph nodes (LNs) in the steady state and shortly after infection with Leishmania major. In the LNs of naive mice, NK cells reside in the medulla and the paracortex, where they closely associate with DCs. In contrast to T cells, intravital microscopy revealed that NK cells in the superficial regions of LNs were slowly motile and maintained their interactions with DCs over extended times in the presence or absence of immune-activating signals. L. major induced NK cells to secrete interferon-γ and to be recruited to the paracortex, where concomitant CD4 T cell activation occurred. Therefore, NK cells form a reactive but low mobile network in a strategic area of the LN where they can receive inflammatory signals, interact with DCs, and regulate colocalized T cell responses.
Published: 2006
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39. Rapamycin inhibits growth and survival of D-816-V-mutated c-kit mast cells

Author: Yves Lepelletier, Olivier Lortholary, Guy Laurent, Martine Humbert, Olivier Hermine, Jean Pierre Zappulla, Antoine Ribadeau-Dumas, Marion Gabillot-Carré, Nadine Ben Hamouda, Paulo de Sepuvelda, Christian Recher, Emmanuel Morelon, Christine Bodemer, François Machavoine, Cédric Baude, Aurélie Hermant, Patrice Dubreuil, Jacques Vargaftig, Michel Arock, Sébastien Letard, Michel Dy, Roland S. Liblau, Ying Yang, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'immunologie, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Cancérologie, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancérologie (Inserm U599/IPC), Université de la Méditerranée - Aix-Marseille 2-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département Immunologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Slama, Catherine, Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, MESH : Brain Mapping, Apoptosis, medicine.disease_cause, Biochemistry, MESH: Magnetic Resonance Imaging, MESH : Auditory Perception, Mice, 0302 clinical medicine, MESH : Tumor Cells, Cultured, MESH : Neural Pathways, MESH : Cell Proliferation, Tumor Cells, Cultured, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, Mast Cells, Systemic mastocytosis, MESH: Mastocytosis, Systemic, MESH: Brain Mapping, MESH : Cell Survival, 0303 health sciences, Mutation, MESH: Music, TOR Serine-Threonine Kinases, MESH : Music, MESH : Mastocytosis, Systemic, MESH: Mast Cells, Hematology, MESH : Mice, Transgenic, MESH: Positron-Emission Tomography, 3. Good health, MESH: Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-kit, MESH: Cell Survival, Phosphorylation, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : Mast Cells, MESH : Pharmacogenetics, Tyrosine kinase, MESH : Time Factors, medicine.drug, Signal Transduction, Cell Survival, MESH: Mice, Transgenic, Immunology, Mutation, Missense, MESH: Acoustic Stimulation, MESH: Pharmacogenetics, Mice, Transgenic, MESH : Protein Kinases, Biology, MESH : Proto-Oncogene Proteins c-kit, MESH : Emotions, 03 medical and health sciences, MESH: Auditory Perception, MESH: Brain, Mastocytosis, Systemic, MESH: Models, Neurological, MESH : Magnetic Resonance Imaging, MESH: Cell Proliferation, MESH : Mice, medicine, MESH : Models, Neurological, Animals, Humans, MESH: Tumor Cells, Cultured, MESH: Mice, MESH: Protein Kinases, PI3K/AKT/mTOR pathway, 030304 developmental biology, Cell Proliferation, MESH: Emotions, MESH : Signal Transduction, Sirolimus, MESH: Mutation, Missense, MESH: Humans, MESH : Sirolimus, MESH: Apoptosis, MESH: Neural Pathways, MESH : Humans, RPTOR, MESH: Time Factors, MESH : Positron-Emission Tomography, Cell Biology, MESH : Acoustic Stimulation, medicine.disease, MESH : Brain, Pharmacogenetics, Cancer research, MESH : Animals, MESH: Sirolimus, Protein Kinases, MESH : Apoptosis, MESH : Mutation, Missense, 030215 immunology
Abstract: International audience; Two classes of oncogenic mutations of the c-kit tyrosine kinase have been described: the juxtamembrane domain V560G mutation, which is preferentially found in gastrointestinal stromal tumors (GISTs), and the kinase domain D816V mutation, which is highly representative of systemic mastocytosis (SM). Here we show that both mutations constitutively activate the mammalian target of rapamycin (mTOR) signaling pathway. Surprisingly, the mTOR inhibitor rapamycin induces only apoptosis in HMC-1 cells bearing the D816V but not the V560G mutation. In support of this unexpected selectivity, rapamycin inhibits the phosphorylation of 4E-BP1, a downstream substrate of the mTOR pathway, but only in D816V HMC-1 cells. Importantly, D816V mast cells isolated from SM patients or from transgenic mice are sensitive to rapamycin whereas normal human or mouse mast cells are not. Thus, rapamycin inhibition appears specific to the D816V mutation. At present there is no effective cure for SM patients with the D816V mutation. The data presented here provide a rationale to test whether rapamycin could be a possible treatment for SM and other hematologic malignancies with the D816V mutation.
Published: 2006
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40. Vitamin E transport in enterocytes

Author: Béatrice Gleize, Xavier Collet, Martina Schneider, Emmanuelle Reboul, Alexis Klein, Alain Margotat, Patrick Borel, Christiane Malezet-Desmoulins, Laurent Lagrost, Florence Bietrix, Nutrition humaine et lipides : Biodisponibilité, métabolisme et régulation, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique ( INRA ) -Université de Provence - Aix-Marseille 1-IFR125-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire des Lipoprotéines humaines et interactions vasculaires, Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Physiopathologie Toulouse Purpan, and Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: CD36 Antigens, Lutein, Time Factors, 030309 nutrition & dietetics, medicine.medical_treatment, alpha-Tocopherol, Tocopherols, MESH : Dose-Response Relationship, Drug, Biochemistry, Intestinal absorption, chemistry.chemical_compound, Mice, Vitamin E, Intestinal Mucosa, MESH : Cholesterol, Micelles, MESH : Intestines, 0303 health sciences, Temperature, Cell Differentiation, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Intestinal epithelium, Lipids, MESH : Mice, Transgenic, MESH : Epithelial Cells, MESH : Enterocytes, MESH : Antigens, CD36, medicine.anatomical_structure, Cholesterol, MESH : Cell Differentiation, medicine.medical_specialty, Enterocyte, Mice, Transgenic, Biology, Binding, Competitive, Article, Absorption, 03 medical and health sciences, Internal medicine, MESH : Mice, MESH : Micelles, medicine, Animals, Humans, RNA, Messenger, Scavenger receptor, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, gamma-Tocopherol, Dose-Response Relationship, Drug, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH : Binding, Competitive, MESH : Humans, MESH : Caco-2 Cells, MESH : Lipids, Biological Transport, Epithelial Cells, Cell Biology, Bioavailability, MESH : Absorption, MESH : Biological Transport, Endocrinology, Enterocytes, chemistry, MESH : Animals, Caco-2 Cells
Abstract: Although cellular uptake of vitamin E was initially described as a passive process, recent studies in the liver and brain have shown that SR-BI (scavenger receptor class B type I) is involved in this phenomenon. As SR-BI is expressed at high levels in the intestine, the present study addressed the involvement of SR-BI in vitamin E trafficking across enterocytes. Apical uptake and efflux of the main dietary forms of vitamin E were examined using Caco-2 TC-7 cell monolayers as a model of human intestinal epithelium. (R,R,R)-gamma-tocopherol bioavailability was compared between wild-type mice and mice overexpressing SR-BI in the intestine. The effect of vitamin E on enterocyte SR-BI mRNA levels was measured by real-time quantitative reverse transcription-PCR. Concentration-dependent curves for vitamin E uptake were similar for (R,R,R)-alpha-, (R,R,R)-gamma-, and dl-alpha-tocopherol. (R,R,R)-alpha-tocopherol transport was dependent on incubation temperature, with a 60% reduction in absorption at 4 degrees C compared with 37 degrees C (p < 0.05). Vitamin E flux in enterocytes was directed from the apical to the basal side, with a relative 10-fold reduction in the transfer process when measured in the opposite direction (p < 0.05). Co-incubation with cholesterol, gamma-tocopherol, or lutein significantly impaired alpha-tocopherol absorption. Anti-human SR-BI antibodies and BLT1 (a chemical inhibitor of lipid transport via SR-BI) blocked up to 80% of vitamin E uptake and up to 30% of apical vitamin E efflux (p < 0.05), and similar results were obtained for (R,R,R)-gamma-tocopherol. SR-BI mRNA levels were not significantly modified after a 24-h incubation of Caco-2 cells with vitamin E. Finally, (R,R,R)-gamma-tocopherol bioavailability was 2.7-fold higher in mice overexpressing SR-BI than in wild-type mice (p < 0.05). The present data show for the first time that vitamin E intestinal absorption is, at least in part, mediated by SR-BI.
Published: 2005
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41. Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation

Author: Roland S. Liblau, Jacques P. Zappulla, Sébastien Letard, Michel Arock, Patrice Dubreuil, Nadine Ben Hamouda, Marc Daëron, Georges Delsol, Sabine Desbois, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancérologie (Inserm U599/IPC), Université de la Méditerranée - Aix-Marseille 2-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Allergologie Moléculaire et Cellulaire, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'immunologie, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Immunologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Slama, Catherine, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cancérologie, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Mutant, Cell Culture Techniques, MESH : Blotting, Western, medicine.disease_cause, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, MESH: Animals, Mast Cells, 0303 health sciences, Mutation, Reverse Transcriptase Polymerase Chain Reaction, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Mast Cells, Hyperplasia, MESH : Mice, Transgenic, 3. Good health, MESH: Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-kit, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA Primers, MESH : Mast Cells, Mastocytosis, Genetically modified mouse, MESH: DNA Primers, MESH : Cell Culture Techniques, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Transgenic, Transgene, Blotting, Western, Immunology, Mutation, Missense, Mice, Transgenic, MESH : Mastocytosis, Biology, MESH : Proto-Oncogene Proteins c-kit, 03 medical and health sciences, MESH : Mice, medicine, Animals, Humans, MESH: Blotting, Western, MESH: Mice, DNA Primers, 030304 developmental biology, MESH: Cell Culture Techniques, MESH: Mutation, Missense, MESH: Humans, Point mutation, MESH : Humans, Brief Definitive Report, medicine.disease, Mast cell sarcoma, Cancer research, MESH: Mastocytosis, MESH : Animals, MESH : Mutation, Missense
Abstract: Mastocytosis is a rare neoplastic disease characterized by a pathologic accumulation of tissue mast cells (MCs). Mastocytosis is often associated with a somatic point mutation in the Kit protooncogene leading to an Asp/Val substitution at position 816 in the kinase domain of this receptor. The contribution of this mutation to mastocytosis development remains unclear. In addition, the clinical heterogeneity presented by mastocytosis patients carrying the same mutation is unexplained. We report that a disease with striking similarities to human mastocytosis develops spontaneously in transgenic mice expressing the human Asp816Val mutant Kit protooncogene specifically in MCs. This disease is characterized by clinical signs ranging from a localized and indolent MC hyperplasia to an invasive MC tumor. In addition, bone marrow–derived MCs from transgenic animals can be maintained in culture for >24 mo and acquire growth factor independency for proliferation. These results demonstrate a causal link in vivo between the Asp816Val Kit mutation and MC neoplasia and suggest a basis for the clinical heterogeneity of human mastocytosis.
Published: 2005
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42. Dynamics of thymus-colonizing cells during human development

Author: Frederic Jourquin, Rima Haddad, Isabelle André-Schmutz, Cecile Schiffer, Micael Yagello, Niclas Setterblad, Emmanuelle Six, Anne-Lise Delezoide, Bruno Canque, Marina Cavazzana-Calvo, Fabien Guimiot, Françoise Pflumio, Jean Claude Gluckman, Edmond Kahn, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Service de Biologie du Développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Commun d'Imagerie Cellulaire et Moléculaire, Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (UMR_S567 / UMR 8104), Saidi, Vanessa, Laboratoire d'Immunologie Cellulaire et Immunopathologie de l'Ecole Pratique des Hautes Etudes, Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Laboratoire d'Imagerie Fonctionnelle ( LIF ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UMR_S567 / UMR 8104 ), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Universitaire d'Hématologie (IUH), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: MESH : Bone Marrow, Antigens, Differentiation, T-Lymphocyte, Pathology, MESH: Hematopoietic Stem Cells, Mice, 0302 clinical medicine, Bone Marrow, Cell Movement, Immunology and Allergy, MESH : Cell Movement, MESH: Animals, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, MESH: Antigens, CD, MESH: Cell Movement, MESH : Organ Culture Techniques, 0303 health sciences, education.field_of_study, B-Lymphocytes, Cell Differentiation, Phenotype, MESH : Mice, Transgenic, Cell biology, Haematopoiesis, MESH : Phenotype, MESH : Antigens, Differentiation, T-Lymphocyte, medicine.anatomical_structure, Infectious Diseases, MESH: Bone Marrow, [SDV.IB]Life Sciences [q-bio]/Bioengineering, MESH : Cell Differentiation, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Mice, Transgenic, T cell, Population, Immunology, Mice, Transgenic, Thymus Gland, Biology, MESH: Phenotype, MESH : B-Lymphocytes, 03 medical and health sciences, Organ Culture Techniques, Antigens, CD, MESH: B-Lymphocytes, MESH : Mice, medicine, MESH : Antigens, CD, Animals, Humans, MESH : Thymus Gland, Progenitor cell, education, MESH: Mice, 030304 developmental biology, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Fetus, MESH: Humans, MESH : Hematopoietic Stem Cells, MESH : Humans, MESH: Thymus Gland, Hematopoietic Stem Cells, MESH: Organ Culture Techniques, MESH: Antigens, Differentiation, T-Lymphocyte, Bone marrow, MESH : Animals, Ex vivo, 030215 immunology
Abstract: SummaryHere, we identify fetal bone marrow (BM)-derived CD34hiCD45RAhiCD7+ hematopoietic progenitors as thymus-colonizing cells. This population, virtually absent from the fetal liver (FL), emerges in the BM by development weeks 8–9, where it accumulates throughout the second trimester, to finally decline around birth. Based on phenotypic, molecular, and functional criteria, we demonstrate that CD34hiCD45RAhiCD7+ cells represent the direct precursors of the most immature CD34hiCD1a− fetal thymocytes that follow a similar dynamics pattern during fetal and early postnatal development. Histological analysis of fetal thymuses further reveals that early immigrants predominantly localize in the perivascular areas of the cortex, where they form a lymphostromal complex with thymic epithelial cells (TECs) driving their rapid specification toward the T lineage. Finally, using an ex vivo xenogeneic thymus-colonization assay, we show that BM-derived CD34hiCD45RAhiCD7+ progenitors are selectively recruited into the thymus parenchyma in the absence of exogenous cytokines, where they adopt a definitive T cell fate.
Published: 2005
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43. Differential requirements for survival and proliferation of CD8 naïve or memory T cells

Author: Corinne Tanchot, François A. Lemonnier, Benedita Rocha, Béatrice Pérarnau, Antonio A. Freitas, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunité Cellulaire Antivirale, Institut Pasteur [Paris], Dynamiques Lymphocytaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Receptors, Antigen, T-Cell, alpha-beta, MESH: T-Lymphocyte Subsets, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Mice, 0302 clinical medicine, T-Lymphocyte Subsets, Cytotoxic T cell, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, MESH: Animals, IL-2 receptor, 0303 health sciences, MESH : Cell Survival, Multidisciplinary, MESH: Receptors, Antigen, T-Cell, alpha-beta, MESH : Adoptive Transfer, CD28, MESH : Cell Division, MESH : CD8-Positive T-Lymphocytes, Adoptive Transfer, MESH: CD8-Positive T-Lymphocytes, MESH : Mice, Transgenic, MESH : Receptors, Antigen, T-Cell, alpha-beta, MESH: Cell Survival, MESH: Immunologic Memory, MESH: Cell Division, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Cell Division, MESH : Immunologic Memory, Cell Survival, MESH: Mice, Transgenic, MESH : Male, H-Y Antigen, Mice, Transgenic, MESH : Mice, Inbred C57BL, Biology, Major histocompatibility complex, MESH: H-2 Antigens, MESH: H-Y Antigen, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MHC class I, MESH : Mice, Animals, Antigen-presenting cell, Histocompatibility Antigen H-2D, MESH: Lymphocyte Activation, MESH: Mice, MESH : H-Y Antigen, MESH : Lymphocyte Activation, 030304 developmental biology, MESH : H-2 Antigens, H-2 Antigens, MHC restriction, MESH : T-Lymphocyte Subsets, MESH: Male, Mice, Inbred C57BL, MESH: Adoptive Transfer, Immunology, biology.protein, MESH : Animals, Immunologic Memory, MESH: Female, CD8, 030215 immunology
Abstract: The requisite molecular interactions for CD8 T cell memory were determined by comparison of monoclonal naı̈ve and memory CD8+T cells bearing the T cell receptor (TCR) for the HY antigen. Naı̈ve T cells required only the right major histocompatibility complex (MHC) class I–restricting molecule to survive; to expand, they also needed antigen. In contrast, for survival, memory cells did not require the restricting MHC allele, but needed only a nonspecific class I; for expansion the correct class I, but not antigen, was required. Thus, maintenance of CD8 T cell memory still required TCR–MHC class I interactions, but memory T cells may have a lower functional activation threshold that facilitates secondary responses.
Published: 1997
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44. Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance

Author: Benedita Rocha, Alf Grandien, Antonio A. Freitas, Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Immunobiologie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Vougny, Marie-Christine
Subjects: Male, MESH : Molecular Sequence Data, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, MESH : Antigens, MESH : Lymphocyte Transfusion, MESH: Base Sequence, Mice, 0302 clinical medicine, Immunology and Allergy, Cytotoxic T cell, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH : Female, IL-2 receptor, MESH: Bone Marrow Transplantation, MESH: Chimera, Bone Marrow Transplantation, 0303 health sciences, MESH: Receptors, Antigen, T-Cell, alpha-beta, biology, MESH : Immune Tolerance, Articles, MESH : Mice, Transgenic, 3. Good health, medicine.anatomical_structure, MESH : Receptors, Antigen, T-Cell, alpha-beta, Lymphocyte Transfusion, MESH: Lymphocyte Transfusion, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Antigens, MESH: Immune Tolerance, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Transgenic, T cell, MESH : Sex Factors, MESH : Male, Immunology, Naive B cell, Molecular Sequence Data, Mice, Transgenic, MESH : Mice, Inbred C57BL, 03 medical and health sciences, Sex Factors, Antigen, MESH: Sex Factors, MESH: Mice, Inbred C57BL, MESH : Mice, medicine, Immune Tolerance, Animals, Antigens, Antigen-presenting cell, MESH: Mice, B cell, 030304 developmental biology, MESH : T-Lymphocytes, CD40, MESH: Molecular Sequence Data, Base Sequence, Chimera, MESH : Bone Marrow Transplantation, Molecular biology, MESH: Male, Mice, Inbred C57BL, MESH: T-Lymphocytes, biology.protein, MESH : Chimera, MESH : Base Sequence, MESH : Animals, MESH: Female, 030215 immunology
Abstract: International audience; We studied the interactions of male-specific T cell receptor (TCR)-alpha/beta-transgenic (TG) cells with different concentrations of male antigen in vivo. We constructed mouse chimeras expressing different amounts of male antigen by injecting thymectomized, lethally irradiated mice with various ratios of male (immunoglobulin [Ig] Ha) and female (IgHb) bone marrow. These chimeras were injected with male-specific TCR-alpha/beta-trangenic cells. These experiments allowed us to monitor antigen persistence and characterize antigen-specific T cells in terms of their frequency, reactivity, and effector functions (as tested by elimination of male B cells in vivo). In the absence of antigen, virgin TG cells persisted but did not expand. Transient exposure to antigen resulted in cell expansion, followed by the persistence of increased numbers of antigen-reactive T cells. In contrast, antigen persistence was followed by two independent mechanisms of tolerance induction: anergy (at high antigen concentrations), where T cells did not differentiate into effector functions but persisted in vivo as unresponsive T cells, and exhaustion (at lower antigen concentrations), where differentiation into effector functions (B cell elimination) occurred but was followed by the disappearance of antigen-specific T cells.
Published: 1995
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45. Stat3 and Gfi-1 Transcription Factors Control Th17 Cell Immunosuppressive Activity via the Regulation of Ectonucleotidase Expression

Author: Bernhard Ryffel, Simon C. Robson, Sylvain Ladoire, Jean René Pallandre, François Ghiringhelli, Lionel Apetoh, Frédérique Végran, Aziz Hichami, Angélique Chevriaux, Gérard Eberl, Christophe Borg, Julie Vincent, Cédric Rébé, Grégoire Mignot, David Masson, Fanny Chalmin, Valentin Derangère, Mélanie Bruchard, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Department of Medicine and Surgery, Harvard Medical School [Boston] ( HMS ) -Beth Israel Deaconess Medical Centre-Liver Center and Transplantation Institute, Développement des Tissus Lymphoïdes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Immunologie et embryologie moléculaires ( IEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Centre-Liver Center and Transplantation Institute, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: Adoptive cell transfer, MESH : Transcription Factors, Cellular differentiation, MESH: Th17 Cells, T-Lymphocytes, Cell, MESH : Promoter Regions, Genetic, MESH : RNA, Small Interfering, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Transforming Growth Factor beta, MESH: RNA, Small Interfering, MESH : STAT3 Transcription Factor, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Ectonucleotidase, MESH: Animals, RNA, Small Interfering, STAT3, MESH: Lymphocytes, Tumor-Infiltrating, Promoter Regions, Genetic, MESH: Antigens, CD, 5'-Nucleotidase, Regulation of gene expression, Mice, Knockout, 0303 health sciences, MESH : Gene Expression Regulation, Apyrase, MESH: STAT3 Transcription Factor, MESH: Transcription Factors, MESH: Gene Expression Regulation, MESH : Mice, Transgenic, Cell biology, MESH : Lymphocytes, Tumor-Infiltrating, DNA-Binding Proteins, MESH : Apyrase, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA-Binding Proteins, MESH: Apyrase, STAT3 Transcription Factor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : Interleukin-6, MESH: Mice, Transgenic, T cell, Immunology, Mice, Transgenic, MESH : Mice, Inbred C57BL, Biology, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, MESH: Mice, Inbred C57BL, Antigens, CD, MESH: Promoter Regions, Genetic, MESH : 5'-Nucleotidase, MESH : Mice, medicine, MESH : Antigens, CD, MESH : Th17 Cells, Animals, Transcription factor, MESH: Mice, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH : T-Lymphocytes, Binding Sites, Interleukin-6, MESH: Interleukin-6, Mice, Inbred C57BL, MESH: T-Lymphocytes, MESH : Transforming Growth Factor beta, MESH: Binding Sites, Gene Expression Regulation, biology.protein, MESH : Mice, Knockout, Th17 Cells, MESH : Animals, MESH: 5'-Nucleotidase, MESH: DNA-Binding Proteins, MESH : Binding Sites, 030215 immunology, Transcription Factors
Abstract: International audience; Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.
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