Descriptor: "MESH: Nerve Tissue Proteins" - Searchworks@Jio Institute Digital Library Search Results

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306 results on '"MESH: Nerve Tissue Proteins"'

1. Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Author: Jean-Yves Hogrel, Myriam Ly-Le Moal, A. Daron, Teresa Gidaro, Timothy Seabrook, Laurent Servais, Carole Vuillerot, Vincent Laugel, Emmanuel Fournier, Pierre G. Carlier, Ulrike Schara, Yann Péréon, Nicole Hellbach, Andreea Mihaela Seferian, Claude Cances, Ksenija Gorni, M. Annoussamy, Linda Lowes, C. Lilien, Ricardo Hermosilla, Christian Czech, Liesbeth De Waele, Institut de Myologie, 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), SYSNAV, Centre Hospitalier Universitaire de Liège (CHU-Liège), Centre de reference des maladies neuromusculaires Nantes-Angers, CHU d'Angers et Nantes, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), 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), University Hospitals Leuven [Leuven], KU Leuven Campus Kulak Kortrijk [Belgium], CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], University of Duisburg-Essen, University of Oxford, Nationwide Children's Hospital, Hoffman-La Roche Ltd, Translational Medicine, Neuroscience, Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Roche Innovation Center [Basel, Switzerland], Pfizer, Gestionnaire, Hal Sorbonne Université, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), CHU Toulouse [Toulouse], Université de Lyon-Université de Lyon-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 de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University of Oxford [Oxford], and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
Subjects: 0301 basic medicine, Vital capacity, Time Factors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medizin, MESH: Respiratory Function Tests, NASAL INSPIRATORY PRESSURE, Severity of Illness Index, Pulmonary function testing, MESH: Magnetic Resonance Imaging, Disability Evaluation, 0302 clinical medicine, MESH: Muscular Atrophy, Spinal, MESH: Child, Longitudinal Studies, MESH: Nerve Tissue Proteins, Child, MESH: Longitudinal Studies, Research Articles, VALUES, General Neuroscience, MESH: Muscle Strength, MESH: Disability Evaluation, RNA-Binding Proteins, SMA, Magnetic Resonance Imaging, MESH: Motor Activity, Respiratory Function Tests, medicine.anatomical_structure, MESH: Young Adult, Child, Preschool, Anesthesia, Disease Progression, Upper limb, MESH: Disease Progression, Erratum, Life Sciences & Biomedicine, RC321-571, Research Article, Adult, Adolescent, Clinical Neurology, Neurosciences. Biological psychiatry. Neuropsychiatry, Nerve Tissue Proteins, Motor Activity, Muscular Atrophy, Spinal, Upper Extremity, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, Statistical significance, MESH: Severity of Illness Index, medicine, Humans, Muscle Strength, RC346-429, MESH: Adolescent, Science & Technology, MESH: Humans, business.industry, MESH: Time Factors, MESH: Child, Preschool, Neurosciences, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Survival of motor neuron, MESH: Adult, Spinal muscular atrophy, MESH: Upper Extremity, medicine.disease, 030104 developmental biology, MESH: RNA-Binding Proteins, Neurology. Diseases of the nervous system, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. METHODS: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo® ), quantitative magnetic resonance imaging (fat fraction [FFT2 ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. RESULTS: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FFT2 increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. INTERPRETATION: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo® enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:8 issue:2 pages:359-373 ispartof: location:United States status: published
Published: 2020

2. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author: James W. Wheless, Thierry Frebourg, Robert Olaso, Rosemarie Smith, Kelly Nori, François Lecoquierre, Delphine Héron, Roseline Caumes, Anne Boland, Ange-Line Bruel, Candy Kumps, Gaël Nicolas, Sarah Stewart, Sophie Rondeau, Diane Doummar, Marlène Rio, Giulia Barcia, Anne-Marie Guerrot, Gwenaël Le Guyader, Alexandra Afenjar, Sarah Vergult, Karine Poirier, Juliette Coursimault, Jennifer Morrison, Amy Kritzer, Anne-Sophie Alaix, Rebecca Hernan, Anne-Sophie Denommé-Pichon, Sabine Sigaudy, Christine Coubes, Pascale Saugier-Veber, Francisca Millan Zamora, Austin Larson, Michelle M. Morrow, Christine Poitou, Björn Menten, Mathilde Nizon, Thomas Smol, Elise Schaefer, Bénédicte Gérard, Charles Coutton, Salima El Chehadeh, Fanggeng Zou, Stéphanie Valence, Anita Shanmugham, Wendy K. Chung, Bert Callewaert, Christina Kresge, Arnold Munnich, Beth A. Pletcher, Laurence Faivre, Estelle Colin, Laurence Colleaux, Patricia G Wheeler, Annelies Dheedene, Frédéric Tran Mau-Them, Jean-François Deleuze, Claude Houdayer, Jeanne Amiel, Frédéric Bilan, Marine Tessarech, Bertrand Isidor, Guillaume Jouret, Cyril Mignot, Benjamin Cogné, Shuxi Liu, Boris Keren, Françoise Devillard, Catherine Schramm, Margaret Helm, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), GeneDx [Gaithersburg, MD, USA], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique médicale d’Alsace, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Sorbonne Université (SU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ghent University Hospital, Columbia University Irving Medical Center (CUIMC), University of Colorado Anschutz [Aurora], University of Tennessee System, Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Université de Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maine Medical Center, Arnold Palmer Hospital, Boston Children's Hospital, National Center of Genetics, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: Male, Bioinformatics, Epilepsy, 0302 clinical medicine, Neurodevelopmental disorder, MESH: Child, Intellectual disability, Missense mutation, MESH: Obesity, MESH: Genetic Variation, MESH: Nerve Tissue Proteins, Child, Genetics (clinical), MESH: Genetic Association Studies, MESH: Heterozygote, 0303 health sciences, MESH: Transcription Factors, MESH: Infant, 3. Good health, Phenotype, MESH: Feeding and Eating Disorders, MESH: Young Adult, Child, Preschool, MESH: Epilepsy, Learning disability, Female, medicine.symptom, Adult, Heterozygote, Adolescent, Language delay, Nerve Tissue Proteins, Biology, MESH: Phenotype, MESH: Language Development Disorders, Feeding and Eating Disorders, Young Adult, 03 medical and health sciences, Genetics, medicine, Humans, Language Development Disorders, Obesity, Genetic Association Studies, 030304 developmental biology, MESH: Neurodevelopmental Disorders, MESH: Adolescent, MESH: Humans, MESH: Child, Preschool, Genetic Variation, Infant, MESH: Adult, medicine.disease, Human genetics, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Autism, MESH: Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.
Published: 2022

3. A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

Author: Alex Pezzotta, Anna Pistocchi, Patrick Mehlen, Andrea Paradisi, Anna Di Matteo, Federico Forneris, Daniele Campolungo, Costanza Giampietro, Elisa Belloni, Gianluca Deflorian, Nina Volf, Antonella Chiapparino, Michael Rehman, William Vermi, Maria Paola Paronetto, Mattia Bugatti, Davide Pradella, Claudia Ghigna, Anne Eichmann, Matteo Campioni, Serena Zacchigna, Luigi Scietti, Paradisi, Andrea, Consiglio Nazionale delle Ricerche (CNR), Università degli Studi di Pavia = University of Pavia (UNIPV), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Università degli Studi di Milano = University of Milan (UNIMI), San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Centre Léon Bérard [Lyon], University of Brescia, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Heidelberg University, Swiss Federal Laboratories for Materials Science and Technology [Dübendorf] (EMPA), International Centre for Genetic Engineering and Biotechnology (ICGEB) (Trieste), Yale School of Medicine [New Haven, Connecticut] (YSM), Università degli studi di Trieste = University of Trieste, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], University of Rome 'Foro Italico', Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Pradella, D., Deflorian, G., Pezzotta, A., Di Matteo, A., Belloni, E., Campolungo, D., Paradisi, A., Bugatti, M., Vermi, W., Campioni, M., Chiapparino, A., Scietti, L., Forneris, F., Giampietro, C., Volf, N., Rehman, M., Zacchigna, S., Paronetto, M. P., Pistocchi, A., Eichmann, A., Mehlen, P., Ghigna, C., University of Pavia, University of Milan, Yale University School of Medicine, University of Trieste, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: Netrin Receptor, Angiogenesis, Regulator, General Physics and Astronomy, Apoptosis, RNA-binding protein, RNA-Binding Protein, 0302 clinical medicine, Netrin, Morphogenesis, RNA Isoforms, MESH: Animals, MESH: Endothelial Cells, MESH: Nerve Tissue Proteins, Zebrafish, Colonic Neoplasm, Endothelial Cell, 0303 health sciences, Multidisciplinary, Neovascularization, Pathologic, Chemistry, MESH: Alternative Splicing, RNA-Binding Proteins, RNA Isoform, Netrin-1, Cell biology, MESH: Survival Analysis, 030220 oncology & carcinogenesis, embryonic structures, Colonic Neoplasms, RNA splicing, Survival Analysi, Netrin Receptors, Human, Gene isoform, animal structures, Blood Vessel, Science, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Neuro-Oncological Ventral Antigen, Morphogenesi, Animals, Humans, Alternative Splicing, Blood Vessels, Endothelial Cells, Survival Analysis, MESH: Zebrafish, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Neovascularization, 030304 developmental biology, Pathologic, MESH: Colonic Neoplasms, MESH: Humans, Animal, MESH: Apoptosis, fungi, Alternative splicing, MESH: Blood Vessels, General Chemistry, MESH: Netrin Receptors, MESH: RNA Isoforms, MESH: Morphogenesis, Exon skipping, MESH: RNA-Binding Proteins, nervous system, MESH: Netrin-1, Nerve Tissue Protein, MESH: Neovascularization, Pathologic, Tumour angiogenesis
Abstract: The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B’s necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis., Nature Communications, 12, ISSN:2041-1723
Published: 2021

4. Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload

Author: Rui Adão, Catherine Rucker-Martin, David Montani, P. Mendes-Ferreira, Mélanie Lambert, Valérie Domergue, Véronique Capuano, Rozenn Quarck, Maria-Rosa Ghigna, Frédéric Perros, Jean-Luc Vachiery, Hélène Leribeuz, Angèle Boet, Carmen Brás-Silva, Marc Humbert, Fabrice Antigny, Quarck, Rozenn, Hôpital Bicêtre, Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Chirurgical Marie Lannelongue (CCML), Universidade do Porto = University of Porto, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Institut Paris Saclay d’Innovation Thérapeutique (IPSIT), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Cliniques Universitaires de Bruxelles [Bruxelles, Belgique], Antigny, Fabrice, and ANR-18-CE14-0023,KAPAH,KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire(2018)
Subjects: MESH: Signal Transduction, 0301 basic medicine, Physiology, [SDV]Life Sciences [q-bio], Proliferation, 030204 cardiovascular system & hematology, K2P3.1, MESH: Ventricular Function, Left, Ventricular Function, Left, Muscle hypertrophy, Ventricular Dysfunction, Left, 0302 clinical medicine, Fibrosis, MESH: Ventricular Dysfunction, Left, MESH: Animals, MESH: Nerve Tissue Proteins, Pulmonary Arterial Hypertension, Ascending-aortic constriction, MESH: Potassium Channels, Tandem Pore Domain, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Ventricular pressure, Cardiology, Rats, Transgenic, Cardiology and Cardiovascular Medicine, MESH: Vascular Remodeling, Signal Transduction, MESH: Pulmonary Arterial Hypertension, medicine.medical_specialty, MESH: Mutation, MESH: Arterial Pressure, MESH: Pulmonary Artery, Concentric hypertrophy, Nerve Tissue Proteins, Pulmonary Artery, Vascular Remodeling, 03 medical and health sciences, Potassium Channels, Tandem Pore Domain, Physiology (medical), Internal medicine, medicine.artery, Ventricular Pressure, medicine, Animals, Arterial Pressure, MESH: Ventricular Pressure, Lung, business.industry, Task-1, medicine.disease, Pulmonary hypertension, PH due to left heart diseases, Disease Models, Animal, 030104 developmental biology, Ventricle, MESH: Rats, Transgenic, Mutation, Pulmonary artery, MESH: Disease Models, Animal, business
Abstract: Aims Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, Group 2 PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, Group 1 PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary vascular and RV levels. However, the role of KCNK3 in the pathobiology of PH due to LHD is unknown. Methods and results We evaluated the role of KCNK3 on PH induced by ascending aortic constriction (AAC), in WT and Kcnk3-LOF-mutated rats, by echocardiography, RV catheterization, histology analyses, and molecular biology experiments. We found that Kcnk3-LOF-mutation had no consequence on the development of left ventricular (LV) compensated concentric hypertrophy in AAC, while left atrial emptying fraction was impaired in AAC-Kcnk3-mutated rats. AAC-animals (WT and Kcnk3-mutated rats) developed PH secondary to AAC and Kcnk3-mutated rats developed more severe PH than WT. AAC-Kcnk3-mutated rats developed RV and LV fibrosis in association with an increase of Col1a1 mRNA in right ventricle and left ventricle. AAC-Kcnk3-mutated rats developed severe pulmonary vascular (pulmonary artery as well as pulmonary veins) remodelling with intense peri-vascular and peri-bronchial inflammation, perivascular oedema, alveolar wall thickening, and exaggerated lung vascular cell proliferation compared to AAC-WT-rats. Finally, in lung, right ventricle, left ventricle, and left atrium of AAC-Kcnk3-mutated rats, we found a strong increased expression of Il-6 and periostin expression and a reduction of lung Ctnnd1 mRNA (coding for p120 catenin), contributing to the exaggerated pulmonary and heart remodelling and pulmonary vascular oedema in AAC-Kcnk3-mutated rats. Conclusions Our results indicate that Kcnk3-LOF is a key event in the pathobiology of PH due to AAC, suggesting that Kcnk3 channel dysfunction could play a potential key role in the development of PH due to LHD.
Published: 2021

5. Pituitary stalk interruption syndrome is characterized by genetic heterogeneity

Author: Joelle Bignon-Topalovic, Ken McElreavey, Raja Brauner, Anu Bashamboo, Fondation Ophtalmologique Adolphe de Rothschild [Paris], Université Paris Descartes - Paris 5 (UPD5), Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This study was supported by Fondation Ophtalmologique Adolphe de Rothschild and Laboratoire Lilly France in the form of funding awarded to RB., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Pituitary gland, Heredity, Pituitary Diseases, 030105 genetics & heredity, Gene mutation, Pathology and Laboratory Medicine, Bioinformatics, Nervous System, Medical Conditions, MESH: Pituitary Gland, MESH: Child, Cryptorchidism, Medicine and Health Sciences, Morphogenesis, MESH: Nerve Tissue Proteins, MESH: Dwarfism, Child, Agenesis of the corpus callosum, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Genetic Association Studies, Pituitary stalk, Heterozygosity, Multidisciplinary, MESH: Infant, Newborn, MESH: Genetic Heterogeneity, MESH: Genetic Predisposition to Disease, Anemia, Hematology, Micropenis, MESH: Infant, 3. Good health, Ectopic Posterior Pituitary, Infectious Diseases, medicine.anatomical_structure, Pituitary Gland, Child, Preschool, Medicine, Female, Anatomy, Pathogens, Research Article, MESH: Pituitary Diseases, MESH: Mutation, Science, Urology, Endocrine System, Dwarfism, Nerve Tissue Proteins, Biology, Genetic Heterogeneity, 03 medical and health sciences, Hypogonadotropic hypogonadism, Congenital Disorders, Genetics, medicine, Humans, Genetic Predisposition to Disease, Birth Defects, Genetic Association Studies, MESH: Humans, Genetic heterogeneity, Hypogonadism, MESH: Child, Preschool, Infant, Newborn, Biology and Life Sciences, Infant, medicine.disease, Hypoglycemia, MESH: Male, Neuroanatomy, Emerging Infectious Diseases, 030104 developmental biology, Metabolic Disorders, Mutation, MESH: Female, Neuroscience, Developmental Biology
Abstract: Pituitary stalk interruption syndrome is a rare disorder characterized by an absent or ectopic posterior pituitary, interrupted pituitary stalk and anterior pituitary hypoplasia, as well as in some cases, a range of heterogeneous somatic anomalies. A genetic cause is identified in only around 5% of all cases. Here, we define the genetic variants associated with PSIS followed by the same pediatric endocrinologist. Exome sequencing was performed in 52 (33 boys and 19 girls), including 2 familial cases single center pediatric cases, among them associated 36 (69.2%) had associated symptoms or syndromes. We identified rare and novel variants in genes (37 families with 39 individuals) known to be involved in one or more of the following—midline development and/or pituitary development or function (BMP4, CDON, GLI2, GLI3, HESX1, KIAA0556, LHX9, NKX2-1, PROP1, PTCH1, SHH, TBX19, TGIF1), syndromic and non-syndromic forms of hypogonadotropic hypogonadism (CCDC141, CHD7, FANCA, FANCC, FANCD2, FANCE, FANCG, IL17RD, KISS1R, NSMF, PMM2, SEMA3E, WDR11), syndromic forms of short stature (FGFR3, NBAS, PRMT7, RAF1, SLX4, SMARCA2, SOX11), cerebellum atrophy with optic anomalies (DNMT1, NBAS), axonal migration (ROBO1, SLIT2), and agenesis of the corpus callosum (ARID1B, CC2D2A, CEP120, CSPP1, DHCR7, INPP5E, VPS13B, ZNF423). Pituitary stalk interruption syndrome is characterized by a complex genetic heterogeneity, that reflects a complex phenotypic heterogeneity. Seizures, intellectual disability, micropenis or cryptorchidism, seen at presentation are usually considered as secondary to the pituitary deficiencies. However, this study shows that they are due to specific gene mutations. PSIS should therefore be considered as part of the phenotypic spectrum of other known genetic syndromes rather than as specific clinical entity.
Published: 2020

6. Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

Author: Le Ribeuz, Hélène, Dumont, Florent, Ruellou, Guillaume, Lambert, Mélanie, Balliau, Thierry, Quatredeniers, Marceau, Girerd, Barbara, Cohen-Kaminsky, Sylvia, Mercier, Olaf, Yen-Nicolaÿ, Stéphanie, Humbert, Marc, Montani, David, Capuano, Véronique, Antigny, Fabrice, Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Génétique Quantitative et Evolution - Le Moulon (Génétique Végétale) (GQE-Le Moulon), AgroParisTech-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, Université Paris-Saclay, Marie Lannelongue Hospital, Therapeutic Innovation Doctoral School (ED569), Région Ile de France (convention n◦ EX024607), ANR-18-CE14-0023,KAPAH,KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire(2018), Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Chirurgical Marie Lannelongue (CCML), Hôpital Bicêtre, Plateforme d'Analyse Protéomique de Paris Sud Ouest (PAPPSO), AgroParisTech, and Antigny, Fabrice
Subjects: Proteomics, MESH: Signal Transduction, Proteome, [SDV]Life Sciences [q-bio], Myocytes, Smooth Muscle, MESH: Pulmonary Artery, Nerve Tissue Proteins, MESH: Molecular Sequence Annotation, Pulmonary Artery, Article, lcsh:Chemistry, Potassium Channels, Tandem Pore Domain, Humans, MESH: Endothelial Cells, MESH: Nerve Tissue Proteins, lcsh:QH301-705.5, Cells, Cultured, proteomic, MESH: Humans, MESH: Proteomics, Computational Biology, Endothelial Cells, MESH: Potassium Channels, Tandem Pore Domain, Molecular Sequence Annotation, MESH: Myocytes, Smooth Muscle, PAH, MESH: Gene Knockdown Techniques, MESH: Gene Expression Regulation, [SDV] Life Sciences [q-bio], MESH: Proteome, Gene Expression Regulation, lcsh:Biology (General), lcsh:QD1-999, Gene Knockdown Techniques, MESH: Biomarkers, Biomarkers, Signal Transduction, MESH: Cells, Cultured, MESH: Computational Biology, potassium channel
Abstract: International audience; The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. Loss of KCNK3 function/expression is a hallmark of PAH. However, the molecular mechanisms involved in KCNK3 dysfunction are mostly unknown. To identify the pathological molecular mechanisms downstream of KCNK3 in human PASMCs (hPASMCs) and human PAECs (hPAECs), we used a Liquid Chromatography-Tandem Mass Spectrometry-based proteomic approach to identify the molecular pathways regulated by KCNK3. KCNK3 loss of expression was induced in control hPASMCs or hPAECs by specific siRNA targeting KCNK3. We found that the loss of KCNK3 expression in hPAECs and hPASMCs leads to 326 and 222 proteins differentially expressed, respectively. Among them, 53 proteins were common to hPAECs and hPASMCs. The specific proteome remodeling in hPAECs in absence of KCNK3 was mostly related to the activation of glycolysis, the superpathway of methionine degradation, and the mTOR signaling pathways, and to a reduction in EIF2 signaling pathways. In hPASMCs, we found an activation of the PI3K/AKT signaling pathways and a reduction in EIF2 signaling and the Purine Nucleotides De Novo Biosynthesis II and IL-8 signaling pathways. Common to hPAECs and hPASMCs, we found that the loss of KCNK3 expression leads to the activation of the NRF2-mediated oxidative stress response and a reduction in the interferon pathway. In the hPAECs and hPASMCs, we found an increased expression of HO-1 (heme oxygenase-1) and a decreased IFIT3 (interferon-induced proteins with tetratricopeptide repeats 3) (confirmed by Western blotting), allowing us to identify these axes to understand the consequences of KCNK3 dysfunction. Our experiments, based on the loss of KCNK3 expression by a specific siRNA strategy in control hPAECs and hPASMCs, allow us to identify differences in the activation of several signaling pathways, indicating the key role played by KCNK3 dysfunction in the development of PAH. Altogether, these results allow us to better understand the consequences of KCNK3 dysfunction and suggest that KCNK3 loss of expression acts in favor of the proliferation and migration of hPASMCs and promotes the metabolic shift and apoptosis resistance of hPAECs.
Published: 2020

7. The Crustacean Hyperglycemic Hormone Superfamily: Progress Made in the Past Decade

Author: Chi-Ying Lee, Jean-Yves Toullec, Hsiang-Yin Chen, Adaptation et diversité en milieu marin (AD2M), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and National Changhua University of Education
Subjects: 0301 basic medicine, Invertebrate Hormones, Endocrinology, Diabetes and Metabolism, Neuropeptide, signaling pathway and receptor, Nerve Tissue Proteins, 030209 endocrinology & metabolism, peptide structure, Review, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Arthropod Proteins, 03 medical and health sciences, Endocrinology, 0302 clinical medicine, Crustacea, MESH: Crustacea, crustacean hyperglycemic hormone superfamily, Animals, MESH: Animals, biological functions, MESH: Nerve Tissue Proteins, Receptor, Gene, structure diversity and evolution, lcsh:RC648-665, biology, biology.organism_classification, MESH: Invertebrate Hormones, Eyestalk, 030104 developmental biology, Evolutionary biology, Multigene Family, [SDE]Environmental Sciences, Ecdysozoa, MESH: Multigene Family, Identification (biology), MESH: Arthropod Proteins, Arthropod, Hormone
Abstract: International audience; Early studies recognizing the importance of the decapod eyestalk in the endocrine regulation of crustacean physiology-molting, metabolism, reproduction, osmotic balance, etc.-helped found the field of crustacean endocrinology. Characterization of putative factors in the eyestalk using distinct functional bioassays ultimately led to the discovery of a group of structurally related and functionally diverse neuropeptides, crustacean hyperglycemic hormone (CHH), molt-inhibiting hormone (MIH), gonad-inhibiting hormone (GIH) or vitellogenesis-inhibiting hormone (VIH), and mandibular organ-inhibiting hormone (MOIH). These peptides, along with the first insect member (ion transport peptide, ITP), constitute the original arthropod members of the crustacean hyperglycemic hormone (CHH) superfamily. The presence of genes encoding the CHH-superfamily peptides across representative ecdysozoan taxa has been established. The objective of this review is to, aside from providing a general framework, highlight the progress made during the past decade or so. The progress includes the widespread identification of the CHH-superfamily peptides, in particular in non-crustaceans, which has reshaped the phylogenetic profile of the superfamily. Novel functions have been attributed to some of the newly identified members, providing exceptional opportunities for understanding the structure-function relationships of these peptides. Functional studies are challenging, especially for the peptides of crustacean and insect species, where they are widely expressed in various tissues and usually pleiotropic. Progress has been made in deciphering the roles of CHH, ITP, and their alternatively spliced counterparts (CHH-L, ITP-L) in the regulation of metabolism and ionic/osmotic hemostasis under (eco)physiological, developmental, or pathological contexts, and of MIH in the stimulation of ovarian maturation, which implicates it as a regulator for coordinating growth (molt) and reproduction. In addition, experimental elucidation of the steric structure and structure-function relationships have given better understanding of the structural basis of the functional diversification and overlapping among these peptides. Finally, an important finding was the first-ever identification of the receptors for this superfamily of peptides, specifically the receptors for ITPs of the silkworm, which will surely give great impetus to the functional study of these peptides for years to come. Studies regarding recent progress are presented and synthesized, and prospective developments remarked upon.
Published: 2020

8. Characterization of Kcnk3 -Mutated Rat, a Novel Model of Pulmonary Hypertension

Author: Thomas Bertero, Catherine Rucker-Martin, David Montani, Laurent Tesson, Marc Humbert, Fabrice Antigny, Frédéric Perros, Séverine Remy, Véronique Capuano, Barbara Girerd, Ignacio Anegon, Boris Manoury, Christine Péchoux, Olaf Mercier, Mélanie Lambert, Valérie Domergue, Morad K. Nakhleh, Aurélie Hautefort, Angèle Boet, Centre chirurgical Marie Lannelongue, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Biologie et physiopathologie cutanées : expression génique, signalisation et thérapie, 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-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre National de la Recherche Scientifique (CNRS), Unité de recherche génomique et physiologie de la lactation (GPL), Institut National de la Recherche Agronomique (INRA), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Détoxication et réparation tissulaire, 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), Centre Chirurgical Marie Lannelongue (CCML), ANR-18-CE14-0025,MatriPHate,Comprendre la dynamique de la niche vasculaire dans l'hypertension pulmonaire.(2018), Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA), Génomique et Physiologie de la Lactation (GPL), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-18-CE14-0025,MATRIPHATE,UNDERSTANDING THE DYNAMIC OF THE VASCULAR NICHE IN PULMONARY HYPERTENSION (PH). MATRIX REPROGRAMMING FORCES PH.(2018), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Hôpital Bicêtre, Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Transgenic Rats and Immunophenomics Platform, Partenaires INRAE, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Université Côte d'Azur (UCA), Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Signalisation et physiopathologie cardiovasculaire (CARPAT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), Fondation du Souffle et Fonds de Dotation Recherche en Sante Respiratoire from the Fondation Lefoulon-Delalande, Fondation Legs Poix, Therapeutic Innovation Doctoral SchoolED569, ANR-18-CE14-0023,KAPAH,KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire(2018), Bertero, Thomas, APPEL À PROJETS GÉNÉRIQUE 2018 - Comprendre la dynamique de la niche vasculaire dans l'hypertension pulmonaire. - - MatriPHate2018 - ANR-18-CE14-0025 - AAPG2018 - VALID, Antigny, Fabrice, and APPEL À PROJETS GÉNÉRIQUE 2018 - KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire - - KAPAH2018 - ANR-18-CE14-0023 - AAPG2018 - VALID
Subjects: 0301 basic medicine, [SDV.BA] Life Sciences [q-bio]/Animal biology, Physiology, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Rats, Sprague-Dawley, 030204 cardiovascular system & hematology, Extracellular matrix, Exon, 0302 clinical medicine, echocardiography, MESH: Animals, exon, MESH: von Willebrand Factor, MESH: Nerve Tissue Proteins, MESH: Action Potentials, ComputingMilieux_MISCELLANEOUS, Cardiopulmonary disease, education.field_of_study, Potassium channel subfamily K member 3, [SDV.BA]Life Sciences [q-bio]/Animal biology, MESH: Potassium Channels, Tandem Pore Domain, MESH: Blood Pressure, MESH: Muscle, Smooth, Vascular, 3. Good health, [SDV] Life Sciences [q-bio], MESH: Vasoconstriction, medicine.symptom, Cardiology and Cardiovascular Medicine, MESH: Mitogen-Activated Protein Kinase 3, MESH: Nitric Oxide Synthase Type III, MESH: Mitogen-Activated Protein Kinase 1, MESH: Rats, extracellular matrix, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, 03 medical and health sciences, medicine, MESH: Lung, MESH: Survivin, education, Gene, Loss function, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Hypertension, Pulmonary, hypoxia, business.industry, MESH: Loss of Function Mutation, Hypoxia (medical), medicine.disease, Pulmonary hypertension, MESH: Male, rats, 030104 developmental biology, Cancer research, MESH: Disease Models, Animal, business, MESH: Female
Abstract: Rationale: Pulmonary arterial hypertension is a severe lethal cardiopulmonary disease. Loss of function mutations in KCNK3 (potassium channel subfamily K member 3) gene, which encodes an outward rectifier K + channel, have been identified in pulmonary arterial hypertension patients. Objective: We have demonstrated that KCNK3 dysfunction is common to heritable and nonheritable pulmonary arterial hypertension and to experimental pulmonary hypertension (PH). Finally, KCNK3 is not functional in mouse pulmonary vasculature. Methods and Results: Using CRISPR/Cas9 technology, we generated a 94 bp out of frame deletion in exon 1 of Kcnk3 gene and characterized these rats at the electrophysiological, echocardiographic, hemodynamic, morphological, cellular, and molecular levels to decipher the cellular mechanisms associated with loss of KCNK3. Using patch-clamp technique, we validated our transgenic strategy by demonstrating the absence of KCNK3 current in freshly isolated pulmonary arterial smooth muscle cells from Kcnk3 -mutated rats. At 4 months of age, echocardiographic parameters revealed shortening of the pulmonary artery acceleration time associated with elevation of the right ventricular systolic pressure. Kcnk3 -mutated rats developed more severe PH than wild-type rats after monocrotaline exposure or chronic hypoxia exposure. Kcnk3 -mutation induced a lung distal neomuscularization and perivascular extracellular matrix activation. Lungs of Kcnk3 -mutated rats were characterized by overactivation of ERK1/2 (extracellular signal–regulated kinase1-/2), AKT (protein kinase B), SRC, and overexpression of HIF1-α (hypoxia-inducible factor-1 α), survivin, and VWF (Von Willebrand factor). Linked with plasma membrane depolarization, reduced endothelial-NOS expression and desensitization of endothelial-derived hyperpolarizing factor, Kcnk3 -mutated rats presented predisposition to vasoconstriction of pulmonary arteries and a severe loss of sildenafil-induced pulmonary arteries relaxation. Moreover, we showed strong alteration of right ventricular cardiomyocyte excitability. Finally, Kcnk3 -mutated rats developed age-dependent PH associated with low serum-albumin concentration. Conclusions: We established the first Kcnk3 -mutated rat model of PH. Our results confirm that KCNK3 loss of function is a key event in pulmonary arterial hypertension pathogenesis. This model presents new opportunities for understanding the initiating mechanisms of PH and testing biologically relevant therapeutic molecules in the context of PH.
Published: 2019

9. Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems

Author: Nicolas Michalski, Christine Petit, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the Prix Emergence of the Agir Pour l'Audition foundation to N.M. and by grants from the French Agence Nationale pour la Recherche (ANR), as part of the second Investissements d'Avenir program (ANR-15-RHUS-0001), the LabEx Lifesenses (ANR-10-LABX-65), the European Research Council (ERC-2011-ADG_294570), the BNP Paribas Foundation, the FAUN Stiftung, and the LHW-Stiftung to C.P., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), michalski, nicolas, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Collège de France - Chaire Génétique et physiologie cellulaire
Subjects: 0301 basic medicine, MESH: Gene Ontology, Auditory Pathways, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, cochlea, Gene regulatory network, MESH: Hearing Disorders, Ion Channels, 0302 clinical medicine, MESH: Sensory Receptor Cells, MESH: Cochlea, MESH: Gene Expression Regulation, Developmental, auditory cortex, MESH: Hair Cells, Auditory, MESH: Animals, MESH: Nerve Tissue Proteins, Hearing Disorders, auditory hindbrain, General Neuroscience, Gene Expression Regulation, Developmental, MESH: Rhombencephalon, MESH: Transcription Factors, Biological Evolution, MESH: Genes, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, MESH: Auditory Pathways, Brainstem, Hair cell, Sensory Receptor Cells, Neurogenesis, Nerve Tissue Proteins, MESH: Biological Evolution, Biology, Auditory cortex, hair cell, 03 medical and health sciences, Hair Cells, Auditory, evolution, medicine, Auditory system, Animals, Humans, Transcription factor, gene regulatory networks, Cochlea, MESH: Humans, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurogenesis, Rhombencephalon, 030104 developmental biology, Gene Ontology, Genes, MESH: Ion Channels, Neuroscience, 030217 neurology & neurosurgery, Function (biology), Transcription Factors
Abstract: International audience; The genetic approach, based on the study of inherited forms of deafness, has proven to be particularly effective for deciphering the molecular mechanisms underlying the development of the peripheral auditory system, the cochlea and its afferent auditory neurons, and how this system extracts the physical parameters of sound. Although this genetic dissection has provided little information about the central auditory system, scattered data suggest that some genes may have a critical role in both the peripheral and central auditory systems. Here, we review the genes controlling the development and function of the peripheral and central auditory systems, focusing on those with demonstrated intrinsic roles in both systems and highlighting the current underappreciation of these genes. Their encoded products are diverse, from transcription factors to ion channels, as are their roles in the central auditory system, mostly evaluated in brainstem nuclei. We examine the on-togenetic and evolutionary mechanisms that may underlie their expression at different sites.
Published: 2019

10. Lobular architecture of human adipose tissue defines the niche and fate of progenitor cells

Author: Christian Dani, A. Remaury, Jean Galitzky, Y. Veeranagouda, A. Briot, Anne Bouloumié, David Estève, M. Didier, Pauline Decaunes, Séverine Ledoux, Nathalie Boulet, Alexia Zakaroff-Girard, C. Belles, Jean-Claude Guillemot, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - 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), Sanofi Aventis R&D [Chilly-Mazarin], Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Biologie Valrose (IBV), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and boulet, nathalie
Subjects: 0301 basic medicine, Cellular differentiation, [SDV]Life Sciences [q-bio], CD34, General Physics and Astronomy, Adipose tissue, 02 engineering and technology, chemistry.chemical_compound, MESH: Transforming Growth Factor beta1, MESH: Alkaline Phosphatase, Adipocyte, Adipocytes, MESH: Obesity, MESH: Nerve Tissue Proteins, Stem Cell Niche, lcsh:Science, Myofibroblasts, Multidisciplinary, Adipogenesis, Stem Cells, Cell Differentiation, 021001 nanoscience & nanotechnology, Cell biology, Extracellular Matrix, [SDV] Life Sciences [q-bio], Adipose Tissue, 0210 nano-technology, Fat metabolism, Myofibroblast, MESH: Adipose Tissue, MESH: Cell Differentiation, Stromal cell, MESH: Myofibroblasts, MESH: Stem Cell Niche, Science, Subcutaneous Fat, Nerve Tissue Proteins, MESH: Stem Cells, Receptors, Nerve Growth Factor, Biology, MESH: Extracellular Matrix, Intra-Abdominal Fat, General Biochemistry, Genetics and Molecular Biology, Article, Transforming Growth Factor beta1, 03 medical and health sciences, MESH: Receptors, Nerve Growth Factor, MESH: Subcutaneous Fat, Humans, Obesity, Progenitor cell, MESH: Intra-Abdominal Fat, MESH: Adipocytes, Progenitor, MESH: Humans, General Chemistry, Alkaline Phosphatase, 030104 developmental biology, chemistry, Mesenchymal stem cells, lcsh:Q, MESH: Adipogenesis
Abstract: Human adipose tissue (hAT) is constituted of structural units termed lobules, the organization of which remains to be defined. Here we report that lobules are composed of two extracellular matrix compartments, i.e., septa and stroma, delineating niches of CD45−/CD34+/CD31− progenitor subsets characterized by MSCA1 (ALPL) and CD271 (NGFR) expression. MSCA1+ adipogenic subset is enriched in stroma while septa contains mainly MSCA1−/CD271− and MSCA1−/CD271high progenitors. CD271 marks myofibroblast precursors and NGF ligand activation is a molecular relay of TGFβ-induced myofibroblast conversion. In human subcutaneous (SC) and visceral (VS) AT, the progenitor subset repartition is different, modulated by obesity and in favor of adipocyte and myofibroblast fate, respectively. Lobules exhibit depot-specific architecture with marked fibrous septa containing mesothelial-like progenitor cells in VSAT. Thus, the human AT lobule organization in specific progenitor subset domains defines the fat depot intrinsic capacity to remodel and may contribute to obesity-associated cardiometabolic risks., In human adipose tissue (AT), adipocytes are organized into units of lobules. Here the authors identify distinct fibrous septal and stromal compartments within AT lobules that differ in composition and potential between subcutaneous and visceral regions and are disturbed in obesity and metabolic syndrome.
Published: 2019

11. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author: Michael R. Brown, Christian Gieger, André G. Uitterlinden, Diana van Heemst, Alison D. Murray, Stephen B. Kritchevsky, Timo A. Lakka, Karen Schwander, Federica Laguzzi, Stephen S. Rich, Rajkumar Dorajoo, Yun Ju Sung, Xiaofeng Zhu, Hugues Aschard, Jing Hua Zhao, Gregory P. Wilson, Kenneth Rice, Barbara Sternfeld, Kent D. Taylor, Paul Elliott, Ei-Ei Khaing Nang, Ilja M. Nolte, Heather M. Stringham, Bruce M. Psaty, Heming Wang, Tangchun Wu, Caroline Hayward, Vilmundur Gudnason, Fernando Pires Hartwig, Paolo Gasparini, Jingjing Liang, Neil Risch, Albertine J. Oldehinkel, Ani Manichaikul, Tibor V. Varga, Michael Y. Tsai, Niek Verweij, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Xiuqing Guo, Traci M. Bartz, Nicholette D. Palmer, Woon-Puay Koh, Rozenn N. Lemaitre, Caizheng Yu, Mike A. Nalls, Mariaelisa Graff, Eric Boerwinkle, Dabeeru C. Rao, Thomas Meitinger, Virginia Fisher, Mario Sims, Charles Kooperberg, Carl D. Langefeld, Jaakko Tuomilehto, Reedik Mägi, Wei Zhao, Wanqing Wen, Donna K. Arnett, Ervin R. Fox, Lynda M. Rose, Maris Alver, Ayse Demirkan, Solomon K. Musani, Dennis O. Mook-Kanamori, Andres Metspalu, Jerome I. Rotter, Barry I. Freedman, Jiang He, Hermina Jakupović, Steven C. Hunt, Marco Brumat, Maria Pina Concas, Rob M. van Dam, Rico Rueedi, Jonathan Marten, Chi Charles Gu, Tõnu Esko, Peter Vollenweider, Zoltán Kutalik, Olli T. Raitakari, Ya X. Wang, Yong-Bing Xiang, Pamela J. Schreiner, Antonietta Robino, Tanika N. Kelly, Igor Rudan, Mathilde Boissel, Claudia Langenberg, Yii-Der Ida Chen, Anne U. Jackson, Lawrence F. Bielak, Brenda W.J.H. Penninx, Brigitte Kühnel, Christopher P. Nelson, Konstantin Strauch, Albert V. Smith, Daniel I. Chasman, Jasmin Divers, Lisa R. Yanek, M. Arfan Ikram, Melissa A. Richard, Nilesh J. Samani, Lisa de las Fuentes, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Yongmei Liu, Peter J. van der Most, Fang-Chi Hsu, Jeffrey R. O'Connell, Alexandre C. Pereira, Raymond Noordam, Changwei Li, Jie Yao, Trudy Voortman, Zhe Wang, Thomas H. Mosley, Diane M. Becker, Charles N. Rotimi, Sami Heikkinen, Archie Campbell, John M. C. Connell, Lenore J. Launer, Hua Tang, Rainer Rauramaa, Ruth J. F. Loos, Pirjo Komulainen, Amy R. Bentley, Patrik Wennberg, Chew-Kiat Heng, Kari E. North, Salman M. Tajuddin, Renée de Mutsert, David J. Porteous, Susan Redline, Sarah E. Harris, Tamara B. Harris, Raha Pazoki, Mickaël Canouil, Robert A. Scott, Jingzhong Ding, Mary F. Feitosa, Jost B. Jonas, José Eduardo Krieger, John M. Starr, Karin Leander, Jennifer A. Smith, Paul W. Franks, Charles B. Eaton, Sharon L.R. Kardia, E. Shyong Tai, Jill M. Norris, Annette Peters, Chiamaka Vivian Nwuba, Jianjun Liu, Stella Aslibekyan, Nora Franceschini, Kurt Lohman, Myriam Fornage, Dina Vojinovic, Erin B. Ware, Xiaoyin Li, Najaf Amin, Johanna Kuusisto, M. Yldau van der Ende, Cora E. Lewis, Lynne E. Wagenknecht, Jennifer G. Robinson, Franco Giulianini, Ulf de Faire, Yechiel Friedlander, Nicholas J. Wareham, Meian He, George J. Papanicolau, Nancy L. Pedersen, Bernardo L. Horta, Karen L. Mohlke, Kelley Pettee Gabriel, Minjung Kho, Michele K. Evans, Ozren Polasek, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Ioanna Ntalla, Cornelia M. van Duijn, L. Adrienne Cupples, Yuri Milaneschi, Stephen Sidney, Alan B. Zonderman, Leo-Pekka Lyytikäinen, Mohsen Ghanbari, Harold Snieder, Donald W. Bowden, Aldi T. Kraja, Alaitz Poveda, Terho Lehtimäki, Paul S. de Vries, Dongfeng Gu, Sotoodehnia Nona, Thomas W. Winkler, Muhammad Riaz, Ian J. Deary, Fumihiko Takeuchi, Pim van der Harst, Alisa K. Manning, Michael A. Province, Andrea R. V. R. Horimoto, David R. Weir, Wei Zheng, Alanna C. Morrison, Marzyeh Amini, Jian-Min Yuan, W. James Gauderman, Paul M. Ridker, Melanie Waldenberger, Chuan Gao, Xiao-Ou Shu, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, Tamar Sofer, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Digital Health, IT University of Copenhagen, Icahn School of Medicine at Mount Sinai [New York] (MSSM), National Institutes of Health [Bethesda] (NIH), Leiden University Medical Center (LUMC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University of Regensburg, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], Queen Mary University of London (QMUL), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), University of Washington [Seattle], The present work was largely supported by a grant from the US National Heart, Lung,and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305)., Kilpeläinen, Tuomas O., Bentley, Amy R., Noordam, Raymond, Sung, Yun Ju, Schwander, Karen, Winkler, Thomas W., Jakupović, Hermina, Chasman, Daniel I., Manning, Alisa, Ntalla, Ioanna, Aschard, Hugue, Brown, Michael R., de las Fuentes, Lisa, Franceschini, Nora, Guo, Xiuqing, Vojinovic, Dina, Aslibekyan, Stella, Feitosa, Mary F., Kho, Minjung, Musani, Solomon K., Richard, Melissa, Wang, Heming, Wang, Zhe, Bartz, Traci M., Bielak, Lawrence F., Campbell, Archie, Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Li, Changwei, Lohman, Kurt K., Marten, Jonathan, Sim, Xueling, Smith, Albert V., Tajuddin, Salman M., Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Evangelou, Evangelo, Gao, Chuan, Graff, Mariaelisa, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Zhao, Jing Hua, Kraja, Aldi T., Kühnel, Brigitte, Laguzzi, Federica, Lyytikäinen, Leo-Pekka, Nolte, Ilja M., Rauramaa, Rainer, Riaz, Muhammad, Robino, Antonietta, Rueedi, Rico, Stringham, Heather M., Takeuchi, Fumihiko, van der Most, Peter J., Varga, Tibor V., Verweij, Niek, Ware, Erin B., Wen, Wanqing, Li, Xiaoyin, Yanek, Lisa R., Amin, Najaf, Arnett, Donna K., Boerwinkle, Eric, Brumat, Marco, Cade, Brian, Canouil, Mickaël, Chen, Yii-Der Ida, Concas, Maria Pina, Connell, John, de Mutsert, Renée, de Silva, H. Janaka, de Vries, Paul S., Demirkan, Ayşe, Ding, Jingzhong, Eaton, Charles B., Faul, Jessica D., Friedlander, Yechiel, Gabriel, Kelley P., Ghanbari, Mohsen, Giulianini, Franco, Gu, Chi Charle, Gu, Dongfeng, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven C., Ikram, M. Arfan, Jonas, Jost B., Koh, Woon-Puay, Komulainen, Pirjo, Krieger, Jose E., Kritchevsky, Stephen B., Kutalik, Zoltán, Kuusisto, Johanna, Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Leander, Karin, Lemaitre, Rozenn N., Lewis, Cora E., Liang, Jingjing, Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, Navis, Gerjan, Rots, Marianne, Swertz, Morri, Wolffenbuttel, Bruce H. R., Wijmenga, Cisca, Liu, Jianjun, Mägi, Reedik, Manichaikul, Ani, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Mohlke, Karen L., Mosley, Thomas H., Murray, Alison D., Nalls, Mike A., Nang, Ei-Ei Khaing, Nelson, Christopher P., Nona, Sotoodehnia, Norris, Jill M., Nwuba, Chiamaka Vivian, O’Connell, Jeff, Palmer, Nicholette D., Papanicolau, George J., Pazoki, Raha, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Porteous, David J., Poveda, Alaitz, Raitakari, Olli T., Rich, Stephen S., Risch, Neil, Robinson, Jennifer G., Rose, Lynda M., Rudan, Igor, Schreiner, Pamela J., Scott, Robert A., Sidney, Stephen S., Sims, Mario, Smith, Jennifer A., Snieder, Harold, Sofer, Tamar, Starr, John M., Sternfeld, Barbara, Strauch, Konstantin, Tang, Hua, Taylor, Kent D., Tsai, Michael Y., Tuomilehto, Jaakko, Uitterlinden, André G., van der Ende, M. Yldau, van Heemst, Diana, Voortman, Trudy, Waldenberger, Melanie, Wennberg, Patrik, Wilson, Gregory, Xiang, Yong-Bing, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., de Faire, Ulf, Deary, Ian J., Elliott, Paul, Esko, Tõnu, Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Kato, Norihiro, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Samani, Nilesh J., Shu, Xiao-Ou, van der Harst, Pim, Van Vliet-Ostaptchouk, Jana V., Vollenweider, Peter, Wagenknecht, Lynne E., Wang, Ya X., Wareham, Nicholas J., Weir, David R., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Evans, Michele K., Franks, Paul W., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kelly, Tanika N., Liu, Yongmei, North, Kari E., Pereira, Alexandre C., Ridker, Paul M., Tai, E. Shyong, van Dam, Rob M., Fox, Ervin R., Kardia, Sharon L. R., Liu, Ching-Ti, Mook-Kanamori, Dennis O., Province, Michael A., Redline, Susan, van Duijn, Cornelia M., Rotter, Jerome I., Kooperberg, Charles B., Gauderman, W. Jame, Psaty, Bruce M., Rice, Kenneth, Munroe, Patricia B., Fornage, Myriam, Cupples, L. Adrienne, Rotimi, Charles N., Morrison, Alanna C., Rao, Dabeeru C., Loos, Ruth J. F., Bentley, Amy R [0000-0002-0827-9101], Jakupović, Hermina [0000-0001-9667-9406], Manning, Alisa [0000-0003-0247-902X], Aschard, Hugues [0000-0003-0907-2548], de Las Fuentes, Lisa [0000-0002-4689-325X], Richard, Melissa [0000-0003-0129-9860], Liu, Ching-Ti [0000-0002-0703-0742], Rice, Kenneth [0000-0002-3071-7278], Munroe, Patricia B [0000-0002-4176-2947], Loos, Ruth JF [0000-0002-8532-5087], Apollo - University of Cambridge Repository, Epidemiology, Radiology & Nuclear Medicine, Erasmus MC other, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, IT University of Copenhagen (ITU), Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Value, Affordability and Sustainability (VALUE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., Navis, G., Rots, M., Swertz, M., Wolffenbuttel, BHR, and Wijmenga, C.
Subjects: Genetics and Molecular Biology (all), Male, Genome-wide association study, 02 engineering and technology, Biochemistry, MESH: Genotype, MESH: Nerve Tissue Proteins, lcsh:Science, MESH: Lipid Metabolism, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Asian Continental Ancestry Group, Kólesteról, Hispanic or Latino, MESH: Transcription Factors, MESH: European Continental Ancestry Group, Lipids, ddc, 3. Good health, REVEAL, Cholesterol, MESH: Young Adult, Science & Technology - Other Topics, MESH: Membrane Proteins, MESH: Cholesterol, HDL, Hispanic Americans, 0210 nano-technology, Erfðarannsóknir, MESH: Cholesterol, LDL, MESH: Triglycerides, Genotype, Genetic Loci, Lipid Metabolism, Science, European Continental Ancestry Group, LIM-Homeodomain Proteins, Locus (genetics), EXERCISE, Adolescent, Adult, African Continental Ancestry Group/genetics, Aged, Asian Continental Ancestry Group/genetics, Brazil, Calcium-Binding Proteins/genetics, Cholesterol/blood, Cholesterol, HDL/blood, Cholesterol, HDL/genetics, Cholesterol, LDL/blood, Cholesterol, LDL/genetics, European Continental Ancestry Group/genetics, Exercise, Female, Genetic Loci/genetics, Genome-Wide Association Study, Hispanic Americans/genetics, Humans, LIM-Homeodomain Proteins/genetics, Lipid Metabolism/genetics, Lipids/blood, Lipids/genetics, Membrane Proteins/genetics, Microtubule-Associated Proteins/genetics, Middle Aged, Muscle Proteins/genetics, Nerve Tissue Proteins/genetics, Transcription Factors/genetics, Triglycerides/blood, Triglycerides/genetics, Young Adult, General Biochemistry, Genetics and Molecular Biology, Article, White People, CARBOXYLASE, 03 medical and health sciences, Physics and Astronomy (all), MESH: Muscle Proteins, Asian People, Lifelines Cohort Study, SNP, METAANALYSIS, Ancestry, MESH: Adolescent, Biochemistry, Genetics and Molecular Biology (all), MESH: Humans, Science & Technology, Calcium-Binding Proteins, MESH: Adult, MESH: Microtubule-Associated Proteins, 030104 developmental biology, chemistry, MESH: Genome-Wide Association Study, lcsh:Q, MESH: African Continental Ancestry Group, Chemistry (all), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Brazil, MESH: Female, Transcription Factors, 0301 basic medicine, General Physics and Astronomy, Blood lipids, Muscle Proteins, MESH: Calcium-Binding Proteins, chemistry.chemical_compound, MESH: Aged, 80 and over, MESH: Cholesterol, WIDE ASSOCIATION, African Continental Ancestry Group, Genetics, MESH: Aged, Multidisciplinary, Public Health, Global Health, Social Medicine and Epidemiology, 021001 nanoscience & nanotechnology, Multidisciplinary Sciences, lipids (amino acids, peptides, and proteins), Medical Genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Microtubule-Associated Proteins, Asian Continental Ancestry Group, Black People, Nerve Tissue Proteins, Biology, MESH: Genetic Loci, MD Multidisciplinary, Triglycerides, Medicinsk genetik, MESH: LIM-Homeodomain Proteins, Triglyceride, MESH: Hispanic Americans, Cholesterol, HDL, Genome-wide analyses, Membrane Proteins, Lipid metabolism, General Chemistry, Cholesterol, LDL, Arfgengi, MESH: Lipids, MESH: Male, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Exercise, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: Publisher's version (útgefin grein), Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels., The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.
Published: 2018

12. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor X (RFX) transcription factors through X-box promoter motifs

Author: Isabel Tapia-Páez, Eero Castrén, Andrea Bieder, Kristiina Tammimies, Debora Sugiaman-Trapman, Gilbert Lauter, Peter Swoboda, Rachel Torchet, Marie-Estelle Hokkanen, Juha Kere, Jan Burghoorn, Neuroscience Center, Eero Castren / Principal Investigator, Research Programs Unit, Juha Kere / Principal Investigator, Research Programme for Molecular Neurology, Karolinska Institutet [Stockholm], University of Helsinki, and This study was supported by the Swedish Brain Foundation (Hjärnfonden ), the Swedish Research Council, the TorstenSöderberg, Ahlén, Lars Hiertas Minne, and Sigrid Jusélius Foundations, the Swedish Foundation for Strategic Research, the Karolinska Institutet (KI) Strategic Neuroscience Program, and the Academy of Finland. This study was performed, in part, at the Live Cell Imaging Unit/Nikon Center of Excellence at the KI Department of Biosciences and Nutrition, which is supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the KI Center for Innovative Medicine, and the Jonasson donation to the School of Technology and Health, Royal Institute of Technology.
Subjects: 0301 basic medicine, C. ELEGANS, Candidate gene, H1T GENE, MESH: Cytoskeletal Proteins, [SDV]Life Sciences [q-bio], ciliary proteins, Biochemistry, READING-DISABILITY, Dyslexia, 0302 clinical medicine, Genes, Reporter, MESH: Animals, MESH: Nerve Tissue Proteins, Promoter Regions, Genetic, [SDV.BDD]Life Sciences [q-bio]/Development Biology, POPULATION, Cells, Cultured, Genetics, Regulation of gene expression, Cilium, Nuclear Proteins, MESH: Regulatory Factor X Transcription Factors, Cell biology, NEURONAL MIGRATION, Microtubule-Associated Proteins, MESH: Cells, Cultured, Biotechnology, MESH: Dyslexia, EXPRESSION, Nerve Tissue Proteins, Regulatory Factor X Transcription Factors, Biology, 03 medical and health sciences, MESH: Cilia, MESH: Caenorhabditis elegans, Ciliogenesis, MESH: Promoter Regions, Genetic, Animals, Humans, Cilia, CELL-TYPES, Caenorhabditis elegans, Molecular Biology, Gene, Transcription factor, CILIOGENESIS, reading disorder, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Binding Sites, Research, MESH: Genes, Reporter, 3112 Neurosciences, MESH: Microtubule-Associated Proteins, Cytoskeletal Proteins, 030104 developmental biology, MESH: Binding Sites, RFX1, DEVELOPMENTAL DYSLEXIA, ciliopathies, hTERT-RPE1 cell line, RFX3, VERTEBRATE, gene regulation, MESH: Nuclear Proteins, 030217 neurology & neurosurgery
Abstract: International audience; DYX1C1, DCDC2, and KIAA0319 are three of the most replicated dyslexia candidate genes (DCGs). Recently, these DCGs were implicated in functions at the cilium. Here, we investigate the regulation of these DCGs by Regulatory Factor X transcription factors (RFX TFs), a gene family known for transcriptionally regulating ciliary genes. We identify conserved X-box motifs in the promoter regions of DYX1C1, DCDC2, and KIAA0319 and demonstrate their functionality, as well as the ability to recruit RFX TFs using reporter gene and electrophoretic mobility shift assays. Furthermore, we uncover a complex regulation pattern between RFX1, RFX2, and RFX3 and their significant effect on modifying the endogenous expression of DYX1C1 and DCDC2 in a human retinal pigmented epithelial cell line immortalized with hTERT (hTERT-RPE1). In addition, induction of ciliogenesis increases the expression of RFX TFs and DCGs. At the protein level, we show that endogenous DYX1C1 localizes to the base of the cilium, whereas DCDC2 localizes along the entire axoneme of the cilium, thereby validating earlier localization studies using overexpression models. Our results corroborate the emerging role of DCGs in ciliary function and characterize functional noncoding elements, X-box promoter motifs, in DCG promoter regions, which thus can be targeted for mutation screening in dyslexia and ciliopathies associated with these genes.-Tammimies, K., Bieder, A., Lauter, G., Sugiaman-Trapman, D., Torchet, R., Hokkanen, M.-E., Burghoorn, J., Castrén, E., Kere, J., Tapia-Páez, I., Swoboda, P. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor (RF) X transcription factors through X-box promoter motifs.
Published: 2016

13. A transgenic mouse expressing CHMP2Bintron5mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia

Author: Frédérique René, Aurelia Vernay, Thiebault Lequeu, Robin Waegaert, Béatrice Blot, François Sellal, Jean-Philippe Loeffler, Rémy Sadoul, Valerie Risson, Sylvie Dirrig-Grosch, Ludivine Therreau, Laurent Schaeffer, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de 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 Mémoire Ressources et Recherche [Strasbourg] (CMRR Strasbourg), CHU Strasbourg, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Dieterle, Stéphane
Subjects: 0301 basic medicine, MESH: Introns, [SDV]Life Sciences [q-bio], MESH: Neurons, MESH: Endosomal Sorting Complexes Required for Transport, Mice, [SCCO]Cognitive science, 0302 clinical medicine, C9orf72, MESH: Behavior, Animal, ALS‐FTD, MESH: Animals, MESH: Nerve Tissue Proteins, Amyotrophic lateral sclerosis, MESH: Amyotrophic Lateral Sclerosis, Genetics (clinical), Neurons, Denervation, Behavior, Animal, Neurodegeneration, neurodegeneration, General Medicine, Anatomy, Sciatic Nerve, MESH: Gene Expression Regulation, Motor coordination, [SDV] Life Sciences [q-bio], MESH: Sciatic Nerve, medicine.anatomical_structure, Frontotemporal Dementia, Frontotemporal dementia, autophagy, MESH: Axons, MESH: Mutation, MESH: Mice, Transgenic, C9ORF72, MESH: Frontotemporal Dementia, Mice, Transgenic, Nerve Tissue Proteins, Biology, 03 medical and health sciences, Genetics, medicine, Animals, Humans, MESH: Mice, Molecular Biology, MESH: Humans, Endosomal Sorting Complexes Required for Transport, Amyotrophic Lateral Sclerosis, [SCCO] Cognitive science, Charged multivesicular body protein 2B, medicine.disease, Spinal cord, Axons, Introns, 030104 developmental biology, Gene Expression Regulation, Mutation, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Mutations in the charged multivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with a mixed ALS-FTD syndrome. To model this syndrome, we generated a transgenic mouse line expressing the human CHMP2Bintron5 mutant in a neuron-specific manner. These mice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reduced muscle strength and decreased motor coordination. CHMP2Bintron5 mice died due to generalized paralysis. When paralyzed, signs of denervation were present as attested by altered electromyographic profiles, by decreased number of fully innervated neuromuscular junctions, by reduction in size of motor endplates and by a decrease of sciatic nerve axons area. However, spinal motor neurons cell bodies were preserved until death. In addition to the motor dysfunctions, CHMP2Bintron5 mice progressively developed FTD-relevant behavioural modifications such as disinhibition, stereotypies, decrease in social interactions, compulsivity and change in dietary preferences. Furthermore, neurons in the affected spinal cord and brain regions showed accumulation of p62-positive cytoplasmic inclusions associated or not with ubiquitin and CHMP2Bintron5 As observed in FTD3 patients, these inclusions were negative for TDP-43 and FUS. Moreover, astrogliosis and microgliosis developed with age. Altogether, these data indicate that the neuronal expression of human CHMP2Bintron5 in areas involved in motor and cognitive functions induces progressive motor alterations associated with dementia symptoms and with histopathological hallmarks reminiscent of both ALS and FTD.
Published: 2016

14. Cone-rod homeobox CRX controls presynaptic active zone formation in photoreceptors of mammalian retina

Author: Robert N. Fariss, Soo-Young Kim, Koray Dogan Kaya, Juthaporn Assawachananont, Anand Swaroop, Jerome E. Roger, National Institutes of Health [Bethesda] (NIH), National Eye Institute [Bethesda, MD, États-Unis] (NEI), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes et de Recherche Thérapeutique en Ophtalmologie (CERTO), Association RETINA France, and Partenaires INRAE-Partenaires INRAE
Subjects: 0301 basic medicine, MESH: Signal Transduction, genetic structures, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Leber Congenital Amaurosis, Ribbon synapse, Mice, 0302 clinical medicine, MESH: Eye Proteins, Retinal Rod Photoreceptor Cells, MESH: Gene Expression Regulation, Developmental, MESH: Leber Congenital Amaurosis, MESH: Presynaptic Terminals, MESH: Animals, Rod cell, MESH: Nerve Tissue Proteins, Genetics (clinical), biology, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Retina, Gene Expression Regulation, Developmental, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cell Differentiation, General Medicine, Cell biology, medicine.anatomical_structure, Retinal Cone Photoreceptor Cells, General Article, Presynaptic active zone, Signal Transduction, MESH: Cell Differentiation, MESH: Mice, Transgenic, MESH: Trans-Activators, Presynaptic Terminals, Mice, Transgenic, Nerve Tissue Proteins, Synaptic vesicle, Retina, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Homeodomain Proteins, Genetics, medicine, Animals, Active zone, Eye Proteins, Molecular Biology, MESH: Mice, MESH: Retinal Rod Photoreceptor Cells, Homeodomain Proteins, Gene Expression Profiling, eye diseases, Disease Models, Animal, 030104 developmental biology, MESH: Retinal Cone Photoreceptor Cells, biology.protein, Trans-Activators, Homeobox, Pikachurin, sense organs, MESH: Disease Models, Animal, 030217 neurology & neurosurgery
Abstract: International audience; In the mammalian retina, rod and cone photoreceptors transmit the visual information to bipolar neurons through highly specialized ribbon synapses. We have limited understanding of regulatory pathways that guide morphogenesis and organization of photoreceptor presynaptic architecture in the developing retina. While neural retina leucine zipper (NRL) transcription factor determines rod cell fate and function, cone-rod homeobox (CRX) controls the expression of both rod- and cone-specific genes and is critical for terminal differentiation of photoreceptors. A comprehensive immunohistochemical evaluation of Crx-/- (null), CrxRip/+ and CrxRip/Rip (models of dominant congenital blindness) mouse retinas revealed abnormal photoreceptor synapses, with atypical ribbon shape, number and length. Integrated analysis of retinal transcriptomes of Crx-mutants with CRX- and NRL-ChIP-Seq data identified a subset of differentially expressed CRX target genes that encode presynaptic proteins associated with the cytomatrix active zone (CAZ) and synaptic vesicles. Immunohistochemistry of Crx-mutant retina validated aberrant expression of REEP6, PSD95, MPP4, UNC119, UNC13, RGS7 and RGS11, with some reduction in Ribeye and no significant change in immunostaining of RIMS1, RIMS2, Bassoon and Pikachurin. Our studies demonstrate that CRX controls the establishment of CAZ and anchoring of ribbons, but not the formation of ribbon itself, in photoreceptor presynaptic terminals.
Published: 2018

15. Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome

Author: Bruno Cavadas, Luísa Pereira, Fanny Koeth, Etienne Simon-Loriere, Marisa Oliveira, Isabelle Casademont, Worachart Lert-itthiporn, Prida Malasit, Orlando Anunciação, Prapat Suriyaphol, Marina Penova, Richard Paul, Fumihiko Matsuda, Chiea Chuen Khor, Ampaiwan Chuansumrit, Kanchana Tangnararatchakit, Anavaj Sakuntabhai, Verónica Fernandes, Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Siriraj Hospital, Mahidol University, Mahidol University [Bangkok], Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pasteur Kyoto International Joint Research Unit for Integrative Vaccinomics [Kyoto, Japan], Institut Pasteur [Paris], Department of Pediatrics, Faculty of Medicine, Mahidol University [Bangkok]-Ramathibodi Hospital, National University of Singapore (NUS), French National Research Agency (ANR-10–INSB–04, Investments for the Future)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Instituto de Investigação e Inovação em Saúde, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Universidade do Porto = University of Porto, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Universidade do Porto [Porto], Genome Institute of Singapore (GIS), Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de Génotypage (CNG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Male, Heredity, Basic Helix-Loop-Helix Transcription Factors / genetics, Thai People, Viral Nonstructural Proteins / genetics, MESH: Asia, Southeastern, Genome-wide association study, Genome, Viral / genetics, Dengue virus, MESH: Dengue Virus, Biochemistry, MESH: Genotype, 0302 clinical medicine, MESH: Basic Helix-Loop-Helix Transcription Factors, Odds Ratio, Ethnicities, Protein Phosphatase 2, MESH: Nerve Tissue Proteins, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Asian Continental Ancestry Group, MESH: Protein Phosphatase 2, Genomics, Genomic Databases, Severe Dengue / ethnology, MESH: Infant, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, MESH: Repressor Proteins, MESH: Young Adult, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Metabolic Pathways, Carrier Proteins / genetics, MESH: Cell Nucleus, MESH: Gene Expression, Genotype, Bioinformatics, lcsh:RC955-962, Single-nucleotide polymorphism, MESH: Severe Dengue, MESH: Carrier Proteins, Serogroup, 03 medical and health sciences, Viral Proteins, Asian People, Sequence Motif Analysis, Cell Nucleus / virology, Genetic predisposition, Genetics, Xenobiotic Metabolism, Humans, MESH: Adolescent, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, MESH: Child, Preschool, Public Health, Environmental and Occupational Health, Biology and Life Sciences, Computational Biology, Infant, MESH: Adult, lcsh:RA1-1270, Dengue Virus, medicine.disease, Tropical Diseases, MESH: Sulfotransferases, MESH: Cell Line, 030104 developmental biology, Severe Dengue / genetics, MESH: Genome-Wide Association Study, MESH: Viral Nonstructural Proteins, Population Groupings, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Carrier Proteins, MESH: Female, 030217 neurology & neurosurgery, 0301 basic medicine, Viral Diseases, Gene Expression, Repressor Proteins / genetics, MESH: Dengue, Viral Nonstructural Proteins, medicine.disease_cause, Dengue fever, Dengue Fever, Geographical Locations, Dengue, Cohort Studies, Database and Informatics Methods, Medicine and Health Sciences, Basic Helix-Loop-Helix Transcription Factors, Nerve Tissue Proteins / genetics, MESH: Cohort Studies, Asia, Southeastern, Type C Phospholipases / genetics, lcsh:Public aspects of medicine, MESH: Genetic Predisposition to Disease, Thailand, Phenotype, Europe, Genetic Mapping, Infectious Diseases, Dengue Virus / genetics, Asian Continental Ancestry Group / genetics, Female, Sulfotransferases, MESH: Genome, Viral, MESH: Type C Phospholipases, Sequence Analysis, Research Article, Neglected Tropical Diseases, Adult, lcsh:Arctic medicine. Tropical medicine, Adolescent, Dengue / virology, Dengue / genetics, Nerve Tissue Proteins, Genome, Viral, Biology, Genetic Predisposition, Research and Analysis Methods, Cell Line, Young Adult, medicine, Viral Proteins / genetics, Genetic Predisposition to Disease, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Severe Dengue, MESH: Thailand, Cell Nucleus, Protein Phosphatase 2 / genetics, MESH: Serogroup, Genome Analysis, MESH: Viral Proteins, MESH: Male, MESH: Odds Ratio, Repressor Proteins, Biological Databases, Metabolism, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Type C Phospholipases, People and Places, Genetics of Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract: Ethnic diversity has been long considered as one of the factors explaining why the severe forms of dengue are more prevalent in Southeast Asia than anywhere else. Here we take advantage of the admixed profile of Southeast Asians to perform coupled association-admixture analyses in Thai cohorts. For dengue shock syndrome (DSS), the significant haplotypes are located in genes coding for phospholipase C members (PLCB4 added to previously reported PLCE1), related to inflammation of blood vessels. For dengue fever (DF), we found evidence of significant association with CHST10, AHRR, PPP2R5E and GRIP1 genes, which participate in the xenobiotic metabolism signaling pathway. We conducted functional analyses for PPP2R5E, revealing by immunofluorescence imaging that the coded protein co-localizes with both DENV1 and DENV2 NS5 proteins. Interestingly, only DENV2-NS5 migrated to the nucleus, and a deletion of the predicted top-linking motif in NS5 abolished the nuclear transfer. These observations support the existence of differences between serotypes in their cellular dynamics, which may contribute to differential infection outcome risk. The contribution of the identified genes to the genetic risk render Southeast and Northeast Asian populations more susceptible to both phenotypes, while African populations are best protected against DSS and intermediately protected against DF, and Europeans the best protected against DF but the most susceptible against DSS., Author summary Dengue fever is endemic in tropical and subtropical areas of East Asia and America, but globalization and climate changes are introducing vector and virus to the naïve regions of Europe and North America. In this work we conducted a statistically robust, coupled association-admixture test in two dengue cohorts from Thailand (classical dengue fever, DF, and dengue shock syndrome, DSS) and a published Vietnamese (DSS only) cohort. We identified new candidate genes associated with DF risk and confirmed known gene family association with DSS risk. In DF, phosphatase control is crucial, including through binding to viral proteins, as we showed for PPP2R5E protein co-localization with DENV1 and DENV2-NS5 proteins within liver cells and differential cellular localizations along time. In DSS, cytokine dynamics, inflammation and activation of vascular endothelium cells are dominant features. The particular genetic risk conferred by these genes indicates that Southeast and Northeast Asians are highly susceptible to both phenotypes, while Africans are best protected against DSS, and Europeans best protected against DF but the most susceptible against DSS.
Published: 2018

16. Modeling amyotrophic lateral sclerosis in pure human iPSc-derived motor neurons isolated by a novel FACS double selection technique

Author: Dorothée Buttigieg, Stéphane Blanchard, Diana Toli, Delphine Bohl, Georg Haase, Gilbert Baillat, Sarah Bellouze, Thomas Lemonnier, Boris Lamotte d'Incamps, Biothérapies pour les Maladies Neurodégénératives, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences de la Timone (INT), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from Agence Nationale pour la Recherche (Modeling ALS with IPS-derived motor neurons, IPSOALS, ANR-08-NEUR-005-02) in the frame of the ERANET-NEURON program. Work in the laboratory of Georg Haase is further financed by CNRS, Aix-Marseille University, Fédération pour la Recherche sur le Cerveau (FRC/Rotary Grant 'Protein aggregates in motoneuron subpopulations: the therapeutic target?'), Association Française contre les Myopathies (AFM grant, 'Motoneuron subpopulations in development and disease'). Work in the laboratory of D. Bohl is supported by INSERM, Institut Pasteur, Agence Nationale de la Recherche (Laboratoire d’Excellence Revive, Investissement d’Avenir, ANR-10-LABX-73), Association Française contre les Myopathies (AFM grant 'Characterisation of pathological defects in motor neurons derived from patients with amyotrophic lateral sclerosis'), Association pour la Recherche sur la Sclerose Laterale Amyotrophique et autres Maladies du Motoneurone (ARS grant 'Human motor neurons genetically reprogrammed from patient fibroblasts: a new approach to analyse ALS physiopathology'), and the Thierry Latran foundation. D. Toli was the recipient of an A.S. Onassis Foundation Scholarship., ANR-09-NEUR-0005,MODDIFSYN(2009), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cell, MESH: Flow Cytometry, MESH: Nerve Degeneration, Superoxide Dismutase-1, Genes, Reporter, MESH: Child, MESH: Nerve Tissue Proteins, Amyotrophic lateral sclerosis (ALS), Axon, Amyotrophic lateral sclerosis, Child, Induced pluripotent stem cell, Cells, Cultured, MESH: Amyotrophic Lateral Sclerosis, MESH: Superoxide Dismutase, MESH: Lentivirus, MESH: Superoxide Dismutase-1, Motor Neurons, Myogenesis, Flow Cytometry, medicine.anatomical_structure, MESH: Cell Survival, Neurology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Motor Neurons, MESH: Cells, Cultured, Adult, Induced pluripotent stem cells (iPSc), Cell death, MESH: Axons, Cell type, Programmed cell death, MESH: Mutation, Axon degeneration, Cell Survival, Induced Pluripotent Stem Cells, Nerve Tissue Proteins, Receptors, Nerve Growth Factor, MESH: Induced Pluripotent Stem Cells, Biology, lcsh:RC321-571, MESH: Coculture Techniques, p75NTR, MESH: Receptors, Nerve Growth Factor, medicine, Humans, Motor neuron disease, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Fluorescent-activated cell sorting (FACS), MESH: Humans, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Lentivirus, MESH: Genes, Reporter, MESH: Adult, Motor neuron, medicine.disease, Axons, Coculture Techniques, MESH: Astrocytes, HB9, nervous system, Astrocytes, Mutation, Nerve Degeneration, Superoxide dismutase 1 (SOD1), Neuroscience
Abstract: International audience; Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease. Human motor neurons generated from induced pluripotent stem cells (iPSc) offer new perspectives for disease modeling and drug testing in ALS. In standard iPSc-derived cultures, however, the two major phenotypic alterations of ALS--degeneration of motor neuron cell bodies and axons--are often obscured by cell body clustering, extensive axon criss-crossing and presence of unwanted cell types. Here, we succeeded in isolating 100% pure and standardized human motor neurons by a novel FACS double selection based on a p75(NTR) surface epitope and an HB9::RFP lentivirus reporter. The p75(NTR)/HB9::RFP motor neurons survive and grow well without forming clusters or entangled axons, are electrically excitable, contain ALS-relevant motor neuron subtypes and form functional connections with co-cultured myotubes. Importantly, they undergo rapid and massive cell death and axon degeneration in response to mutant SOD1 astrocytes. These data demonstrate the potential of FACS-isolated human iPSc-derived motor neurons for improved disease modeling and drug testing in ALS and related motor neuron diseases.
Published: 2015

17. Autosomal recessive primary microcephaly due to ASPM mutations: An update

Author: Martine Doco-Fenzy, Monique Elmaleh-Bergès, Berten Ceulemans, Sandrine Passemard, David Geneviève, Anita Rauch, Daniel Amram, Anais Ernault, Bernd Wollnick, Christine Francannet, Alain Verloes, Abdelaziz Sefiani, Pascaline Letard, Julie Désir, Marc Abramowicz, Brigitte Benzacken, Clothilde Rivier-Ringenbach, Toni Kasole Lubala, Yusuf Tunca, Vincent El Ghouzzi, Mathilde Nizon, Laurence Faivre, Marion Gérard, Koenraad Devriendt, Nathalie Pouvreau, Sophie Guilmin Crepon, Massimiliano Rossi, Hélène Maurey, C. Geoffrey Woods, Julia Metreau, Séverine Drunat, Michèle Mathieu-Dramard, Yves Sznajer, Cyril Gitiaux, Tiffany Busa, Geneviève Pierquin, Corinne Alberti, Sabine Sigaudy, Elise Schaefer, Stéphanie Arpin, Sébastien Lebon, Marta Bertoli, Pierre Gressens, Sophie Julia, Siham Chafai Elalaoui, Sarah Duerinckx, Sanaa Nasserereddine, Yoann Vial, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université libre de Bruxelles (ULB), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Mohamed V, Rabat, Maroc, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), 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), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lubumbashi (UNILU), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Ibn Rochd [Casablanca], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Liège (CHU-Liège), L'Hôpital Nord-Ouest [Villefranche sur Saône], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Université Catholique de Louvain = Catholic University of Louvain (UCL), Gülhane School of Medicine, Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Georg-August-University = Georg-August-Universität Göttingen, University of Cambridge [UK] (CAM), University hospital of Zurich [Zurich], Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Paris 13 (UP13), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), CHU Clermont-Ferrand, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Toulouse [Toulouse], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Lubumbashi, Georg-August-University [Göttingen], Richard, Nicolas, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Jean Verdier, UFR Santé, Médecine et Biologie Humaine ( UFR SMBH ), Université Paris 13 ( UP13 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Hôpital Bretonneau-CHRU Tours, Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Reims ( CHU Reims ), Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Hospices Civils de Lyon ( HCL ), Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique 1426 ( CIC 1426 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Passemard, Sandrine [0000-0002-0242-4566], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Microcephaly, MESH: Geography, Intellectual disability, ASPM, brain development, brain imaging, MESH: Cognition, [SDV.GEN] Life Sciences [q-bio]/Genetics, Spindle pole body, MESH: Magnetic Resonance Imaging, Cohort Studies, Neurodevelopmental disorder, Cognition, MESH: Nerve Tissue Proteins, MESH: Cohort Studies, Genetics (clinical), MESH: Genetic Association Studies, Genetics, 0303 health sciences, Geography, primary microcephaly, 030305 genetics & heredity, Brain development, MESH: Infant, Magnetic Resonance Imaging, 3. Good health, intellectual disability, Child, Preschool, Autosomal Recessive Primary Microcephaly, Brain size, Female, MESH: Mutation, Brain imaging, Nerve Tissue Proteins, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Microcephaly, Primary microcephaly, 03 medical and health sciences, medicine, Humans, Family, Gene, MESH: Family, Genetic Association Studies, 030304 developmental biology, Centrosome, MCPH, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genetic heterogeneity, MESH: Child, Preschool, Infant, medicine.disease, MESH: Male, 030104 developmental biology, centrosome, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Human medicine, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female
Abstract: Autosomal recessive microcephaly or MicroCephaly Primary Hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The Abnormal SPindle-like Microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities. This article is protected by copyright. All rights reserved. ispartof: Human Mutation vol:39 issue:3 pages:319-332 ispartof: location:United States status: published
Published: 2017

18. Complex formation with pentraxin-2 regulates factor X plasma levels and macrophage interactions

Author: Peter J. Lenting, Véronique Regnault, Olivier D. Christophe, Cécile V. Denis, Gabriel Aymé, Paulette Legendre, Amélie Harel, Vincent Muczynski, Cécile Loubière, Marc Vasse, Amine Bazaa, Delphine Borgel, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Inovarion SAS, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Hôpital Foch [Suresnes], Service d'immuno-hématologie pédiatrique [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), REGNAULT, Véronique, AYME, Gabriel, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Vitamin K, [SDV]Life Sciences [q-bio], Gene Expression, MESH: Factor X, Plasma protein binding, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Mice, Knockout, Biochemistry, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: RNA, Small Interfering, MESH: Animals, MESH: Nerve Tissue Proteins, RNA, Small Interfering, Internalization, Receptor, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Factor X Deficiency, MESH: Organ Specificity, media_common, Mice, Knockout, MESH: Kinetics, Chemistry, Factor X, Scavenger Receptors, Class A, Hematology, Endocytosis, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV] Life Sciences [q-bio], C-Reactive Protein, Organ Specificity, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: HEK293 Cells, MESH: Endocytosis, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Protein Binding, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, MESH: Gene Expression, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunoprecipitation, media_common.quotation_subject, Immunology, Nerve Tissue Proteins, MESH: Anticoagulants, MESH: Factor X Deficiency, [SDV.SP.PG] Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, Cell Line, 03 medical and health sciences, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, MESH: Mice, Inbred C57BL, MESH: C-Reactive Protein, MESH: Protein Binding, Animals, Humans, Scavenger receptor, MESH: Mice, MESH: Humans, Macrophages, HEK 293 cells, MESH: Macrophages, MESH: Vitamin K, Anticoagulants, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Cell Biology, Molecular biology, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, MESH: Scavenger Receptors, Class A, MESH: Cell Line, Mice, Inbred C57BL, Kinetics, [SDV.SP.PG]Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, HEK293 Cells, 030104 developmental biology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030215 immunology
Abstract: International audience; Recently, we have identified scavenger receptor class A member I (SR-AI) as a receptor for coagulation factor X (FX), mediating the formation of an FX reservoir at the macrophage surface. Here, we demonstrate that the FX/SR-AI-complex comprises a third protein, pentraxin-2 (PTX2). The presence of PTX2 is essential to prevent internalization of FX by SR-AI, and the presence of FX is needed to interfere with internalization of PTX2. Binding studies showed that FX, SR-AI, and PTX2 independently bind to each other (KD,app: 0.2-0.7 μM). Surprisingly, immunoprecipitation experiments revealed that FX and PTX2 circulate as a complex in plasma, and complex formation involves the FX activation peptide. No binding of PTX2 to other vitamin K–dependent proteins was observed. Short hairpin RNA–mediated inhibition of PTX2 levels in mice resulted not only in reduced levels of PTX2, but also in similarly reduced FX levels. Moreover, PTX2 and FX levels were correspondingly reduced in SR-AI–deficient mice. Analysis of 71 human plasma samples uncovered a strong correlation between FX and PTX2 plasma levels. Furthermore, plasma samples of patients with reduced FX levels (congenital/acquired FX deficiency or after anti–vitamin K treatment) were characterized by concomitantly decreased PTX2 levels. In conclusion, we identified PTX2 as a novel partner for FX, and both proteins cooperate to prevent their SR-AI–mediated uptake by macrophages. Interestingly, their respective plasma levels are interdependent. These findings seem of relevance in perspective of ongoing clinical trials, in which plasma depletion of PTX2 is used as a therapeutical approach in the management of systemic amyloidosis.
Published: 2017

19. Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity

Author: Jan Schmoranzer, Jan Walcher, Diana Hoffmann, Gary R. Lewin, Caglar Gök, Valérie Bégay, André Lampe, Edgar Specker, Simone Pifferi, Raluca Fleischer, Cristina Picci, Volker Haucke, Mirko Moroni, Rohini Kuner, Martin Neuenschwander, Kate Poole, Ewan St. John Smith, Liudmila Lapatsina, Kiran Kumar Bali, Johannes Kühnemund, Luc Estebanez, James F.A. Poulet, Christiane Wetzel, Jens Peter von Kries, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Universita degli Studi di Cagliari [Cagliari], Neuroscience Research Center and Cluster of Excellence NeuroCure, Institute of Pharmacology, Heidelberg Universit, Leibniz-Institut für Molekulare Pharmakologie, Department of Pharmacology - University of Cambridge, University of Cambridge [UK] (CAM), Unité de Neurosciences Information et Complexité [Gif sur Yvette] (UNIC), Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institute of Pharmacology, Heidelberg University, Freie Universität Berlin, Department of Physiology and EMBL Australia Node for Single Molecule Science, Smith, Ewan St John [0000-0002-2699-1979], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Diabetic neuropathy, sensing ion channels, spared nerve injury, neuropathic pain, induced hyperalgesia, touch sensation, sensory neurons, mouse, rat, mechanotransduction, piezo2, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gating, Mechanotransduction, Cellular, Ion Channels, MESH: Sensory Receptor Cells, Ganglia, Spinal, MESH: Animals, MESH: Nerve Tissue Proteins, Mechanotransduction, Skin, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Chemistry, General Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH: Touch, 3. Good health, Touch Perception, MESH: Ganglia, Spinal, MESH: Membrane Proteins, medicine.symptom, Mechanoreceptors, Sensory Receptor Cells, MESH: Mice, Transgenic, MESH: Hypersensitivity, Sensory system, Mice, Transgenic, Nerve Tissue Proteins, 03 medical and health sciences, MESH: Skin, In vivo, MESH: Mice, Inbred C57BL, medicine, Hypersensitivity, Animals, Ion channel, MESH: Mechanotransduction, Cellular, MESH: Mechanoreceptors, Membrane Proteins, Nerve injury, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Touch, MESH: Ion Channels, Neuroscience
Abstract: International audience; The skin is equipped with specialized mechanoreceptors that allow the perception of the slightest brush. Indeed, some mechanoreceptors can detect even nanometer-scale movements. Movement is transformed into electrical signals via the gating of mechanically activated ion channels at sensory endings in the skin. The sensitivity of Piezo mechanically gated ion channels is controlled by stomatin-like protein-3 (STOML3), which is required for normal mechanoreceptor function. Here we identify small-molecule inhibitors of STOML3 oligomerization that reversibly reduce the sensitivity of mechanically gated currents in sensory neurons and silence mechanoreceptors in vivo. STOML3 inhibitors in the skin also reversibly attenuate fine touch perception in normal mice. Under pathophysiological conditions following nerve injury or diabetic neuropathy, the slightest touch can produce pain, and here STOML3 inhibitors can reverse mechanical hypersensitivity. Thus, small molecules applied locally to the skin can be used to modulate touch and may represent peripherally available drugs to treat tactile-driven pain following neuropathy.
Published: 2017
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20. The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations

Author: Thomas Bourgeron, Philippe Faure, Tobias M. Boeckers, Elodie Ey, Nicolas Torquet, Anne-Marie Le Sourd, Claire S. Leblond, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Fondation de France, bythe ANR FLEXNEURIM [ANR09BLAN034003], by the ANR [ANR-08-MNPS-037-01–SynGen], by Neuron-ERANET (EUHF-AUTISM), by the Fondation Orange, by the Fondation FondaMentale, by the Fondation Bettencourt–Schueller. The research leading to these results has also received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution, ANR-09-BLAN-0340,FLEXNEURIM,Neurobiologie intégrative des comportements flexibles dans des modèles animaux par imagerie computationnelle : application en conditions normales et pathologiques(2009), ANR-08-MNPS-0037,SynGen-ASD-LD,Genes synaptiques de l'autisme et du retard mental(2008), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, medicine.medical_specialty, Vocal communication, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Autistic Disorder, MESH: Vocalization, Animal, Nerve Tissue Proteins, Audiology, Biology, Mouse model, 03 medical and health sciences, Mice, Behavioral Neuroscience, 0302 clinical medicine, ProSAP1/Shank2, medicine, Animals, In patient, MESH: Animals, MESH: Nerve Tissue Proteins, Autistic Disorder, Autism spectrum disorder, MESH: Mice, 030304 developmental biology, 0303 health sciences, Communication, business.industry, Ultrasonic vocalization, Communication defects, medicine.disease, MESH: Male, SHANK2, Synaptic protein, Disease Models, Animal, Autism, Ultrasonic sensor, Vocalization, Animal, MESH: Disease Models, Animal, business, 030217 neurology & neurosurgery, Peak frequency
Abstract: International audience; Mouse ultrasonic vocalisations have been often used as a paradigm to extrapolate vocal communication defects observed in patients with autism spectrum disorders (ASD). The role of these vocalisations as well as their development, structure and informational content, however, remain largely unknown. In the present study, we characterised in depth the emission of pup and adult ultrasonic vocalisations of wild-type mice and their ProSAP1/Shank2(-/-) littermates lacking a synaptic scaffold protein mutated in ASD. We hypothesised that the vocal behaviour of ProSAP1/Shank2(-/-) mice not only differs from the vocal behaviour of their wild-type littermates in a quantitative way, but also presents more qualitative abnormalities in temporal organisation and acoustic structure. We first quantified the rate of emission of ultrasonic vocalisations, and analysed the organisation of vocalisations sequences using Markov models. We subsequently measured duration and peak frequency characteristics of each ultrasonic vocalisation, to characterise their acoustic structure. In wild-type mice, we found a high level of organisation in sequences of ultrasonic vocalisations, suggesting a communicative function in this complex system. Very limited significant sex-related variations were detected in their usage and acoustic structure, even in adult mice. In adult ProSAP1/Shank2(-/-) mice, we found abnormalities in the call usage and the structure of ultrasonic vocalisations. Both ProSAP1/Shank2(-/-) male and female mice uttered less vocalisations with a different call distribution and at lower peak frequency in comparison with wild-type littermates. This study provides a comprehensive framework to characterise abnormalities of ultrasonic vocalisations in mice and confirms that ProSAP1/Shank2(-/-) mice represent a relevant model to study communication defects.
Published: 2013
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21. Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome

Author: Aurélie Poulet, Alexandra Benchoua, Richard Delorme, Laure Chatrousse, Francis Cogé, Delphine Héron, Frédérique Rodet-Amsellem, Millan Mark, Claire Boissart, Thomas Bourgeron, Hélène Darville, Anselme L. Perrier, Caroline Nava, Julie Pernelle, Margot Jarrige, Marc Peschanski, Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, French Biodiversity Agency, Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Hydrosystèmes et Bioprocédés (UR HBAN), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Division of General Internal Medicine (DGIM), Université de Genève = University of Geneva (UNIGE), Institut de Recherche Servier, SERVIER, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This study has been in part funded by grants from 'Investissements d'Avenir' – (ANR-11-INBS-0009 - INGESTEM – and ANR-11-INBS-0011 - NeurATRIS), the French National Research Agency ANR (ANR-13-SAMA-0006, SynDivAutism), the Laboratory of Excellence GENMED (ANR-10-LABX-0013), the Bettencourt-Schueller Foundation, the Cognacq Jay Foundation, and the Fondamental Foundation. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository, as well as clinical data. NINDS Repository sample numbers corresponding to the samples used are GM 1869., The authors are thankful to I-Stem's HTS platform staff for constant technical support. We thank the cell bank of Pitié-Salpétrière hospital and the Clinical Investigation Center of Robert Debré hospital for assistance with patient recruitment, information, sampling and fibroblast preparation. H.D. received a PhD grant from Servier's Laboratories. I-Stem is part of the Biotherapies Institute for Rare Diseases (BIRD) supported by the Association Française contre les Myopathies (AFM-Téléthon)., ANR-11-INBS-0009,INGESTEM,INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES(2011), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), d'Eggis, Gilles, Infrastructures - INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES - - INGESTEM2011 - ANR-11-INBS-0009 - INBS - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Santé Mentale et Addictions - Diversité Synaptique dans l'autisme - - SynDivAutism2013 - ANR-13-SAMA-0006 - SAMENTA - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, CHU Pitié-Salpêtrière [APHP], Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], 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)-CHU Pitié-Salpêtrière [APHP], University of Geneva [Switzerland], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris], ANR-11-INBS-0009/11-INBS-0009,INGESTEM,INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES(2011), ANR-11-INBS-0011/11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, GAS, Global Assessment Scale, 0301 basic medicine, VPA, valproic acid, Autism Spectrum Disorder, Cellular differentiation, Autism, Human Embryonic Stem Cells, Drug repurposing, MESH: Neurons, lcsh:Medicine, hESC, human embryonic stem cells, Haploinsufficiency, Severity of Illness Index, RPM, Raven's progressive matrices, MESH: Nerve Tissue Proteins, MESH: Neuronal Plasticity, Induced pluripotent stem cell, SHANK3, Cells, Cultured, ASD, autism spectrum disorders, Neurons, ADOS, Autism Diagnosis Observational Scale, Genetics, MESH: Autism Spectrum Disorder, lcsh:R5-920, Neuronal Plasticity, PPVT, Peabody Picture Vocabulary Test, PSC, pluripotent stem cells, Cell Differentiation, General Medicine, Neural stem cell, 3. Good health, Drug repositioning, Phenotype, Autism spectrum disorder, MESH: Pluripotent Stem Cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Haploinsufficiency, lcsh:Medicine (General), Research Paper, MESH: Cells, Cultured, Pluripotent Stem Cells, MESH: Cell Differentiation, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Nerve Tissue Proteins, ADHD, Attention Deficit Hyperactive Disorder, Lithium, SHANK3, SH3 and multiple ankyrin repeat domains 3, MESH: Phenotype, General Biochemistry, Genetics and Molecular Biology, iPSC, induced pluripotent stem cells, 03 medical and health sciences, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, High throughput screening, MESH: Severity of Illness Index, medicine, Humans, NSC, neural stem cells, RNA, Messenger, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], HTS, high throughput screening, MESH: RNA, Messenger, Valproate, MESH: Humans, MESH: Lithium, business.industry, Valproic Acid, MESH: Transcriptome, lcsh:R, MESH: Human Embryonic Stem Cells, medicine.disease, FDA, Food and Drug Administration, Embryonic stem cell, MESH: Male, DMSO, dimethylsulfoxyde, PPIA, Peptidylprolyl Isomerase A, 030104 developmental biology, SRS, Social Responsiveness Scale, Transcriptome, business, Neuroscience, MESH: Valproic Acid
Abstract: Autism spectrum disorders affect millions of individuals worldwide, but their heterogeneity complicates therapeutic intervention that is essentially symptomatic. A versatile yet relevant model to rationally screen among hundreds of therapeutic options would help improving clinical practice. Here we investigated whether neurons differentiated from pluripotent stem cells can provide such a tool using SHANK3 haploinsufficiency as a proof of principle. A library of compounds was screened for potential to increase SHANK3 mRNA content in neurons differentiated from control human embryonic stem cells. Using induced pluripotent stem cell technology, active compounds were then evaluated for efficacy in correcting dysfunctional networks of neurons differentiated from individuals with deleterious point mutations of SHANK3. Among 202 compounds tested, lithium and valproic acid showed the best efficacy at corrected SHANK3 haploinsufficiency associated phenotypes in cellulo. Lithium pharmacotherapy was subsequently provided to one patient and, after one year, an encouraging decrease in autism severity was observed. This demonstrated that pluripotent stem cell-derived neurons provide a novel cellular paradigm exploitable in the search for specific disease-modifying treatments., Highlights • Human neurons were used to screen for compounds correcting symptoms associated with SHANK3 haploinsufficiency syndrome. • Screening criteria were the ability to increase SHANK3 expression and to increase glutamatergic transmission. • Selected hit compounds were then validated using neurons differentiated from individuals with SHANK3 disrupting mutations. • Lithium was selected and delivered to one of SHANK3 patient showing encouraging positive clinical outcomes after one year. The clinical heterogeneity between individuals affected by autism makes it difficult to anticipate the effectiveness of a treatment. Furthermore, clinical practice lacks biological tools to help make such decisions. Here we use neurons, produced from pluripotent stem cells derived from patients affected by SHANK3 haploinsufficiency syndrome, to test the efficiency of therapeutic compounds. We screened the biological activity of more than 200 compounds on SHANK3 expression. Lithium was ultimately selected and delivered to one patient with a SHANK3-disruptive mutation. This resulted in a positive outcome, as determined by improved autistic core symptoms, thus supporting the usefulness of this type of predictive approach.
Published: 2016

22. Mutations in the Human ROBO1 Gene in Pituitary Stalk Interruption Syndrome

Author: Nasser Moussi, Anu Bashamboo, Joelle Bignon-Topalovic, Raja Brauner, Ken McElreavey, Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Université Paris Descartes - Paris 5 (UPD5), This work was supported by Laboratoire Lilly France, EuroDSD in the European Community’s Seventh Framework Programme FP7/2007–2013 under Grant 201444 (to K.M. and A.B.) and Projet Blanc Institut Pasteur/Assistance Publique-Hôpitaux de Paris 2011 under Grant 295097 (to K.M. and R.B.)., and European Project: 201444,EC:FP7:HEALTH,FP7-HEALTH-2007-A,EURODSD(2008)
Subjects: 0301 basic medicine, Male, Pituitary gland, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Hypopituitarism, MESH: Hypopituitarism, Biochemistry, 0302 clinical medicine, Endocrinology, MESH: Pituitary Gland, MESH: Syndrome, MESH: Nerve Tissue Proteins, Receptors, Immunologic, Exome sequencing, MESH: Infant, Newborn, MESH: Genetic Predisposition to Disease, Micropenis, Aplasia, Syndrome, MESH: Infant, Hypoplasia, 3. Good health, Ectopic Posterior Pituitary, Pedigree, medicine.anatomical_structure, Pituitary Gland, Female, MESH: Rare Diseases, medicine.medical_specialty, MESH: Pedigree, Mutation, Missense, Context (language use), Nerve Tissue Proteins, Sampling Studies, 03 medical and health sciences, Rare Diseases, MESH: Sampling Studies, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, MESH: Receptors, Immunologic, MESH: Mutation, Missense, MESH: Humans, business.industry, Biochemistry (medical), Infant, Newborn, Infant, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, medicine.disease, MESH: Male, 030104 developmental biology, business, MESH: Female, 030217 neurology & neurosurgery
Abstract: Context Pituitary stalk interruption syndrome (PSIS) is characterized by a thin or absent pituitary stalk usually in association with an ectopic posterior pituitary and hypoplasia/aplasia of the anterior pituitary. Associated phenotypes include varied ocular anomalies, hypoglycemia, micropenis/cryptorchidism, growth failure, or combined pituitary hormone deficiencies. Although genetic causes have been identified, they explain only around 5% of PSIS cases. Objective To identify genetic causes of PSIS by exome sequencing. Design Exon enrichment was performed using the Agilent SureSelect Human All Exon V4. Paired-end sequencing was performed on the Illumina HiSeq2000 platform with an average sequencing coverage of ×50. Patients Patients with unexplained PSIS were included in the study. Results In five cases of unexplained PSIS including two familial cases, we identified a novel heterozygous frameshift and nonsense and missense mutations in the ROBO1 gene (p.Ala977Glnfs*40, two affected sibs; p.Tyr1114Ter, sporadic case, and p.Cys240Ser, affected child and paternal aunt) that controls embryonic axon guidance, and branching in the nervous system. Interestingly, four of the five cases of PSIS also presented with ocular anomalies, including hypermetropia with strabismus as well as ptosis. Conclusions These data suggest that mutations in ROBO1 contribute to PSIS and associated ocular anomalies.
Published: 2016

23. Inflammation-induced subventricular zone dysfunction leads to olfactory deficits in a targeted mouse model of multiple sclerosis

Author: Kazuaki Yoshikawa, Pierre-Marie Lledo, Brahim Nait-Oumesmar, Vanja Tepavcevic, Françoise Lazarini, Anne Baron-Van Evercooren, Clara Alfaro-Cervello, José Manuel García-Verdugo, Christophe Kerninon, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), Perception et Mémoire, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Institute for Protein Research [Osaka], Osaka University [Osaka], Instituto Cavanilles Biodiversidad y Biologia Evolutiva, University of Valencia, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by INSERM, the European Leukodystrophy Association (ELA), Ecole des Neurosciences de Paris (ENP), French Society for Multiple Sclerosis (ARSEP), Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Red de Terapia Celular, Consellería de Educación (PROMETEO), and the life insurance company Aprionis. V. Tepavcevic was supported by UPMC, Fondation pour la Recherche Médicale (FRM), Novartis, and COST Action MYELINET BM0604 and NEURINFNET BM0603. B. Nait-Oumesmar and A. Baron-Van Evercooren are recipients of a Contrat d’Interface AP-HP (Fédération de Neurologie, Hôpital Pitié-Salpêtrière, Paris)., Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Lazarini, Françoise
Subjects: MESH: Neural Stem Cells, MESH: Adult Stem Cells, multiple sclerosis, Corpus Callosum, Mice, Olfaction Disorders, 0302 clinical medicine, Neural Stem Cells, Lateral Ventricles, MESH: Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Transcription Factors, MESH: Olfaction Disorders, MESH: Animals, MESH: Nerve Tissue Proteins, Stem Cell Niche, MESH: Lateral Ventricles, 0303 health sciences, Neurogenesis, MESH: Oligodendroglia, MESH: Transcription Factors, General Medicine, Anatomy, Olfactory Bulb, MESH: Interneurons, MESH: Gene Expression Regulation, Neural stem cell, adult neurogenesis, Adult Stem Cells, Oligodendroglia, medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, olfaction, Adult stem cell, MESH: Olfactory Bulb, Encephalomyelitis, Autoimmune, Experimental, Memory, Long-Term, MESH: Stem Cell Niche, Subventricular zone, Nerve Tissue Proteins, Olfaction, Biology, MESH: Corpus Callosum, 03 medical and health sciences, Neuroblast, Interneurons, MESH: Homeodomain Proteins, MESH: Memory, Long-Term, medicine, Animals, Humans, Cell Lineage, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Olfactory memory, MESH: Encephalomyelitis, Autoimmune, Experimental, MESH: Mice, 030304 developmental biology, Homeodomain Proteins, MESH: Humans, MESH: Multiple Sclerosis, Oligodendrocyte Transcription Factor 2, MESH: Cell Lineage, MESH: Neurogenesis, Olfactory bulb, MESH: Astrocytes, Disease Models, Animal, Gene Expression Regulation, nervous system, Astrocytes, MESH: Disease Models, Animal, Neuroscience, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Neural stem cells (NSCs) persist in defined brain niches, including the subventricular zone (SVZ), throughout adulthood and generate new neurons destined to support specific neurological functions. Whether brain diseases such as multiple sclerosis (MS) are associated with changes in adult NSCs and whether this might contribute to the development and/or persistence of neurological deficits remains poorly investigated. We examined SVZ function in mice in which we targeted an MS-like pathology to the forebrain. In these mice, which we refer to herein as targeted EAE (tEAE) mice, there was a reduction in the number of neuroblasts compared with control mice. Altered expression of the transcription factors Olig2 and Dlx2 in the tEAE SVZ niche was associated with amplification of pro-oligodendrogenic transit-amplifying cells and decreased neuroblast generation, which resulted in persistent reduction in olfactory bulb neurogenesis. Altered SVZ neurogenesis led to impaired long-term olfactory memory, mimicking the olfactory dysfunction observed in MS patients. Importantly, we also found that neurogenesis was reduced in the SVZ of MS patients compared with controls. Thus, our findings suggest that neuroinflammation induces functional alteration of adult NSCs that may contribute to olfactory dysfunction in MS patients.
Published: 2011

24. Molecular Physiology of pH-Sensitive Background K2P Channels

Author: Jacques Barhanin, Florian Lesage, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)
Subjects: MESH: Hydrogen-Ion Concentration, Physiology, Molecular Sequence Data, MESH: Neurons, Nerve Tissue Proteins, MESH: Amino Acid Sequence, Biology, MESH: Mice, Knockout, Mice, 03 medical and health sciences, Potassium Channels, Tandem Pore Domain, 0302 clinical medicine, Animals, Humans, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Secretion, Amino Acid Sequence, MESH: Nerve Tissue Proteins, MESH: Mice, Peptide sequence, Gene, 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, MESH: Humans, MESH: Molecular Sequence Data, Channel gating, MESH: Potassium Channels, Tandem Pore Domain, Hydrogen-Ion Concentration, Potassium channel, Biochemistry, Molecular physiology, Biophysics, 030217 neurology & neurosurgery
Abstract: Background K2P channels are tightly regulated by different stimuli including variations of external and internal pH. pH sensitivity relies on proton-sensing residues that influence channel gating and activity. Gene inactivation in the mouse is a revealing implication of K2P channels in many physiological functions ranging from hormone secretion to central respiratory adaptation. Surprisingly, only a few phenotypic traits of these mice have yet been directly related to the pH sensitivity of K2P channels.
Published: 2011

25. Novel roles for Slits and netrins: axon guidance cues as anticancer targets?

Author: Céline Delloye-Bourgeois, Alain Chédotal, Patrick Mehlen, 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Apoptose Cancer et Développement, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, 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), Equipe 1, and 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)
Subjects: MESH: Axons, Deleted in Colorectal Cancer, General Mathematics, Nerve Tissue Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Plasma protein binding, Biology, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Neoplasms, Netrin, Animals, Humans, MESH: Protein Binding, MESH: Animals, MESH: Neoplasms, MESH: Tumor Suppressor Proteins, Nerve Growth Factors, MESH: Nerve Tissue Proteins, Receptor, 030304 developmental biology, Genetics, 0303 health sciences, MESH: Humans, MESH: Nerve Growth Factors, Tumor Suppressor Proteins, Applied Mathematics, Netrin-1, Slit, Axons, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, Roundabout, Suppressor, Axon guidance, Protein Binding
Abstract: International audience; Over the past few years, several genes, proteins and signalling pathways that are required for embryogenesis have been shown to regulate tumour development and progression by playing a major part in overriding antitumour safeguard mechanisms. These include axon guidance cues, such as Netrins and Slits. Netrin 1 and members of the Slit family are secreted extracellular matrix proteins that bind to deleted in colorectal cancer (DCC) and UNC5 receptors, and roundabout receptors (Robos), respectively. Their expression is deregulated in a large proportion of human cancers, suggesting that they could be tumour suppressor genes or oncogenes. Moreover, recent data suggest that these ligand-receptor pairs could be promising targets for personalized anticancer therapies.
Published: 2011

26. 1p19q LOH patterns and expression of p53 and Olig2 in gliomas: relation with histological types and prognosis

Author: Alain Chaunavel, Isabelle Pommepuy, Nicolas Weinbreck, Franck Sturtz, Karine Durand, Sylvie Bourthoumieu, Angélique Guillaudeau, François Labrousse, Rafaël DeArmas, Sandrine Robert, François Caire, Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Université de Limoges (UNILIM), Service d'Histologie, cytologie, cytogénétique, biologie cellulaire [CHU Limoges], Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de Neurochirurgie [CHU Limoges], Service de Biochimie et Génétique Moléculaire [CHU Limoges], Biomolécules Thérapies anti-tumorales (EA4021), and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)
Subjects: Male, Pathology, MESH: Chromosomes, Human, Pair 19, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Loss of Heterozygosity, Kaplan-Meier Estimate, MESH: Gene Amplification, Polymerase Chain Reaction, MESH: Glioma, Loss of heterozygosity, 0302 clinical medicine, MESH: Basic Helix-Loop-Helix Transcription Factors, Gene duplication, Basic Helix-Loop-Helix Transcription Factors, Oligodendroglial Tumor, MESH: In Situ Hybridization, Fluorescence, MESH: Nerve Tissue Proteins, MESH: Tumor Suppressor Protein p53, In Situ Hybridization, Fluorescence, MESH: Aged, 0303 health sciences, MESH: Middle Aged, medicine.diagnostic_test, Brain Neoplasms, Glioma, Middle Aged, Prognosis, Immunohistochemistry, ErbB Receptors, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Adult, medicine.medical_specialty, MESH: Chromosomes, Human, Pair 1, Nerve Tissue Proteins, MESH: Receptor, Epidermal Growth Factor, In situ hybridization, Biology, MESH: Prognosis, Pathology and Forensic Medicine, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, medicine, Humans, MESH: Kaplan-Meier Estimate, Aged, 030304 developmental biology, MESH: Loss of Heterozygosity, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Gene Amplification, Chromosome, MESH: Adult, MESH: Immunohistochemistry, MESH: Polymerase Chain Reaction, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Oligodendrocyte Transcription Factor 2, medicine.disease, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Tumor Markers, Biological, Cancer research, MESH: Microsatellite Repeats, Tumor Suppressor Protein p53, MESH: Female, Chromosomes, Human, Pair 19, Microsatellite Repeats, Fluorescence in situ hybridization
Abstract: International audience; In glial tumors, the loss of heterozygosity of the 1p and 19q chromosomal arms is thought to be a marker of good prognosis in oligodendroglial tumors. However, 1p and 19q loss of heterozygosity may be telomeric, interstitial, centromeric or affect the whole arm of the chromosome and the associations between these different patterns and tumor type, other molecular markers and patient prognosis remain unclear. We analyzed microsatellite markers in a region spanning the chromosome from the telomere to the centromere, to characterize the pattern of 1p and 19q loss of heterozygosity in 39 infiltrative gliomas, including astrocytomas, glioblastomas, oligoastrocytomas and oligodendrogliomas. We then studied the association between loss of heterozygosity and the expression of p53 protein and Olig2, as analyzed using immunohistochemistry, and epidermal growth factor receptor (EGFR) gene amplification, as investigated using fluorescence in situ hybridization (FISH). Finally, we assessed the influence of molecular markers on the overall survival of patients. We identified five different 1p19q loss of heterozygosity patterns among the tumors studied and found that loss of heterozygosity over the whole 1p arm was associated with loss of heterozygosity over the whole 19q arm in 90% of cases. 1p19q whole loss was present in all the classical oligodendrogliomas, whereas other 1p19q loss patterns predominated in oligoastrocytomas. 1p19q whole loss was also significantly associated with Olig2 overexpression, but was never observed in tumors overexpressing p53 protein. We also found that, among patients with contrast-enhancing tumors, those with 1p19q whole loss tended to survive for longer. In combination with classical histological and immunohistochemical data, 1p19q status determination provides pertinent information useful for (1) discriminating between histological types of gliomas and (2) identifying a subgroup of tumors that are associated with a better prognosis.
Published: 2010

27. Role of Fgf8 signalling in the specification of rostral Cajal-Retzius cells

Author: Céline Zimmer, François Guillemot, Silvia Arber, Jun Lee, Alessandra Pierani, Sonia Garel, Amelie Griveau, Institut Jacques Monod (IJM (UMR_7592)), and Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, Telencephalon, EMX2, Fibroblast growth factor, Mice, 0302 clinical medicine, MESH: Animals, MESH: Nerve Tissue Proteins, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Cells, Cultured, In Situ Hybridization, Research Articles, Cerebral Cortex, 0303 health sciences, education.field_of_study, Cerebrum, MESH: Transcription Factors, Anatomy, Marginal zone, Immunohistochemistry, Cell biology, DNA-Binding Proteins, medicine.anatomical_structure, Cerebral cortex, embryonic structures, MESH: Kruppel-Like Transcription Factors, MESH: Cells, Cultured, Signal Transduction, animal structures, Fibroblast Growth Factor 8, MESH: Mice, Transgenic, Population, Kruppel-Like Transcription Factors, Mice, Transgenic, Nerve Tissue Proteins, Biology, 03 medical and health sciences, MESH: In Situ Hybridization, FGF8, Zinc Finger Protein Gli3, Fate mapping, MESH: Homeodomain Proteins, medicine, Animals, education, MESH: Mice, Molecular Biology, 030304 developmental biology, Homeodomain Proteins, MESH: Embryo, Mammalian, MESH: Fibroblast Growth Factor 8, MESH: Immunohistochemistry, Embryo, Mammalian, MESH: Cerebral Cortex, MESH: Telencephalon, MESH: DNA-Binding Proteins, 030217 neurology & neurosurgery, Transcription Factors, Developmental Biology
Abstract: International audience; Cajal-Retzius (CR) cells play a key role in the formation of the cerebral cortex. These pioneer neurons are distributed throughout the cortical marginal zone in distinct graded distributions. Fate mapping and cell lineage tracing studies have recently shown that CR cells arise from restricted domains of the pallial ventricular zone, which are associated with signalling centres involved in the early regionalisation of the telencephalic vesicles. In this study, we identified a subpopulation of CR cells in the rostral telencephalon that expresses Er81, a downstream target of Fgf8 signalling. We investigated the role of the rostral telencephalic patterning centre, which secretes FGF molecules, in the specification of these cells. Using pharmacological inhibitors and genetic inactivation of Fgf8, we showed that production of Fgf8 by the rostral telencephalic signalling centre is required for the specification of the Er81+ CR cell population. Moreover, the analysis of Fgf8 gain-of-function in cultivated mouse embryos and of Emx2 and Gli3 mutant embryos revealed that ectopic Fgf8 signalling promotes the generation of CR cells with a rostral phenotype from the dorsal pallium. These data showed that Fgf8 signalling is both required and sufficient to induce rostral CR cells. Together, our results shed light on the mechanisms specifying rostral CR cells and further emphasise the crucial role of telencephalic signalling centres in the generation of distinct CR cell populations.
Published: 2010

28. Numb Promotes an Increase in Skeletal Muscle Progenitor Cells in the Embryonic Somite

Author: Ana Cumano, Shahragim Tajbakhsh, Pierre Rocheteau, Barbara Gayraud-Morel, Aurélie Jory, Isabelle Le Roux, Michel Cohen-Tannoudji, Cellules Souches et Développement, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique Fonctionnelle de la Souris, Développement des Lymphocytes, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), LSHG-CT-2004-511978 and LHSB-CT-2003-503005, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Muscle Fibers, Skeletal, MESH: Flow Cytometry, Muscle Development, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Animals, MESH: Nerve Tissue Proteins, In Situ Hybridization, Genetics, 0303 health sciences, MESH: Muscle Fibers, Skeletal, Myogenesis, Reverse Transcriptase Polymerase Chain Reaction, Stem Cells, Flow Cytometry, Immunohistochemistry, Cell biology, medicine.anatomical_structure, Somites, embryonic structures, Molecular Medicine, MESH: Muscle Development, [SDV.IMM]Life Sciences [q-bio]/Immunology, MYF5, MESH: Membrane Proteins, Stem cell, animal structures, MESH: Mice, Transgenic, Recombinant Fusion Proteins, Blotting, Western, Green Fluorescent Proteins, Notch signaling pathway, Mitosis, Mice, Transgenic, Nerve Tissue Proteins, MESH: Stem Cells, Biology, MESH: Somites, 03 medical and health sciences, MESH: Green Fluorescent Proteins, MESH: In Situ Hybridization, medicine, MESH: Recombinant Fusion Proteins, Animals, MESH: Blotting, Western, Progenitor cell, MESH: Mice, 030304 developmental biology, Skeletal muscle, Membrane Proteins, MESH: Immunohistochemistry, Cell Biology, MESH: Mitosis, Embryonic stem cell, NUMB, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Multiple cell types arise from cells in the dermomyotome of the somite that express Pax3 and Pax7, and myogenesis is regulated by Notch signaling. The asymmetric cell fate determinant Numb is thought to promote differentiation of skeletal muscle and other lineages by negatively regulating Notch signaling. We used transgenesis to overexpress Numb spatiotemporally in Pax3+/Pax7+ somitic stem and progenitor cells in mouse embryos using a spatiotemporally regulated enhancer element from the Myf5 locus that can target muscle progenitor cells prior to cell commitment. Molecular analyses as well as examination of dermal and skeletal muscle cell fates in vivo show that although Numb is thought to be associated with muscle differentiation, unexpectedly the common stem/progenitor pool size for these lineages is increased in Numb-transgenic embryos. Prospective isolation of the relevant transgenic cells and analysis by quantitative reverse-transcription polymerase chain reaction demonstrated that, in this context, canonical Notch targets are not significantly downregulated. These findings were corroborated using a Notch reporter mouse during the formation of somites and prior to lineage segregation. Thus, we propose that Numb can regulate the self-renewal of dermal and muscle progenitors during a lineage progression. Disclosure of potential conflicts of interest is found at the end of this article.
Published: 2009
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29. Granule cell dispersion develops without neurogenesis and does not fully depend on astroglial cell generation in a mouse model of temporal lobe epilepsy

Author: Christophe Heinrich, Fumio Suzuki, Naoki Nitta, Hisao Hirai, Department of Neurosurgery, Shiga University of Medical Science, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Koto Memorial Hospital, and Deransart, Colin
Subjects: MESH: Cell Death, Doublecortin Domain Proteins, Male, MESH: Hippocampus, Time Factors, MESH: Neurons, MESH: Radiation, Hippocampus, Cell Count, Kainate receptor, MESH: Neuropeptides, Mice, 0302 clinical medicine, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Bromodeoxyuridine, Neurons, MESH: Statistics, Nonparametric, 0303 health sciences, Kainic Acid, Radiation, Cell Death, biology, Neurogenesis, Age Factors, Neural stem cell, Granule cell dispersion, Neurology, MESH: Epilepsy, Temporal Lobe, Microtubule-Associated Proteins, medicine.medical_specialty, Nerve Tissue Proteins, MESH: Phosphopyruvate Hydratase, Statistics, Nonparametric, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Analysis of Variance, MESH: Cell Proliferation, Internal medicine, Glial Fibrillary Acidic Protein, medicine, Animals, Progenitor cell, MESH: Mice, Cell Proliferation, 030304 developmental biology, MESH: Age Factors, Analysis of Variance, MESH: Cell Count, Dentate gyrus, MESH: Time Factors, Neuropeptides, MESH: Kainic Acid, MESH: Male, Doublecortin, MESH: Astrocytes, Mice, Inbred C57BL, MESH: Microtubule-Associated Proteins, Disease Models, Animal, Endocrinology, Bromodeoxyuridine, Epilepsy, Temporal Lobe, Astrocytes, Phosphopyruvate Hydratase, biology.protein, Neurology (clinical), MESH: Disease Models, Animal, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; PURPOSE: Granule cell dispersion (GCD) appears as a characteristic morphological feature of the mesial temporal lobe epilepsy (MTLE). It has been suggested that this phenomenon could be due to an increased neurogenesis in the dentate gyrus. However, this hypothesis is still debated and recent clinical and experimental studies have shown that neurogenesis is rather decreased in MTLE. To further determine the role of neural and astroglial cell generation in GCD we examined the consequences of aging and irradiation, which are known to reduce progenitor cells, in a mouse model of MTLE induced by intrahippocampal kainate (KA) injection. METHODS: We injected KA in hippocampus of three different types of mice; (1) young adult, (2) aged, and (3) irradiated mice. Newly generated cells were labeled by Bromodeoxyuridine (BrdU) and were characterized by immunohistochemistry. The extent of GCD was compared among the three animal groups. RESULTS: In young adult mice, BrdU-labeled neurons as well as doublecortin- and NeuroD-positive cells decreased progressively after KA injection whereas BrdU-labeled astrocytes and microglias increased. In aged and irradiated mice, where basal neurogenesis was already strongly reduced, GCD developed after KA injection to the same extent as in young adult mice. However, augmentation of the BrdU-labeled astrocytes after KA was less than 40% in irradiated mice in comparison to young and aged mice. CONCLUSIONS: Our data show that GCD occurs without neurogenesis. Furthermore GCD developed regardless of the degree of astroglial cell proliferation, suggesting that neural stem cell generation is not crucial for GCD.
Published: 2008

30. Role of Endogenous Brain-Derived Neurotrophic Factor and Sortilin in B Cell Survival

Author: Ahmed Boumediene, Anne-Laure Fauchais, Marie-Odile Jauberteau, Marie-Claude Lise, Fabrice Lalloué, Elisabeth Vidal, Jean-Louis Preud'homme, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de Médecine interne A et polyclinique médicale [CHU Limoges], CHU Limoges, Université de Limoges (UNILIM), Service d'Immunologie et immunogénétique [CHU Limoges], Laboratoire Immunologie et Immunopathologie (ESA 6031), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre National de la Recherche Scientifique (CNRS), and Merigaud, Françoise
Subjects: MESH: Membrane Glycoproteins, Apoptosis, Tropomyosin receptor kinase B, MESH: Brain-Derived Neurotrophic Factor, Receptor, Nerve Growth Factor, 0302 clinical medicine, Neurotrophic factors, MESH: Up-Regulation, Immunology and Allergy, Low-affinity nerve growth factor receptor, MESH: Nerve Tissue Proteins, MESH: Stress, Physiological, Receptor, Cells, Cultured, B-Lymphocytes, 0303 health sciences, Membrane Glycoproteins, biology, Up-Regulation, Cell biology, Autocrine Communication, medicine.anatomical_structure, MESH: Cell Survival, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Receptor Protein-Tyrosine Kinases, MESH: Cells, Cultured, Neurotrophin, medicine.medical_specialty, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cell Survival, Immunology, Nerve Tissue Proteins, 03 medical and health sciences, Stress, Physiological, MESH: B-Lymphocytes, Cell Line, Tumor, Internal medicine, medicine, Humans, Autocrine signalling, B cell, 030304 developmental biology, Brain-derived neurotrophic factor, MESH: Humans, MESH: Apoptosis, Brain-Derived Neurotrophic Factor, MESH: Receptor, Nerve Growth Factor, Receptor Protein-Tyrosine Kinases, MESH: Adaptor Proteins, Vesicular Transport, Adaptor Proteins, Vesicular Transport, Endocrinology, nervous system, biology.protein, MESH: Autocrine Communication, 030217 neurology & neurosurgery
Abstract: Brain-derived neurotrophic factor (BDNF), a major neuronal growth factor, is also known to exert an antiapoptotic effect in myeloma cells. Whereas BDNF secretion was described in B lymphocytes, the ability of B cells to produce sortilin, its transport protein, was not previously reported. We studied BDNF production and the expression of its receptors, tyrosine protein kinase receptor B and p75 neurotrophin receptor in the human pre-B, mature, and plasmacytic malignant B cell lines under normal and stress culture conditions (serum deprivation, Fas activation, or their combination). BDNF secretion was enhanced by serum deprivation and exerted an antiapoptotic effect, as demonstrated by neutralization experiments with antagonistic Ab. The precursor form, pro-BDNF, also secreted by B cells, decreases under stress conditions in contrast to BDNF production. Stress conditions induced the membranous expression of p75 neurotrophin receptor and tyrosine protein kinase receptor B, maximal in mature B cells, contrasting with the sequestration of both receptors in normal culture. By blocking Ab and small interfering RNA, we evidenced that BDNF production and its survival function are depending on sortilin, a protein regulating neurotrophin transport in neurons, which was not previously described in B cells. Therefore, in mature B cell lines, an autocrine BDNF production is up-regulated by stress culture conditions and exerts a modulation of apoptosis through the sortilin pathway. This could be of importance to elucidate certain drug resistances of malignant B cells. In addition, primary B lymphocytes contained sortilin and produced BDNF after mitogenic activation, which suggests that sortilin and BDNF might be implicated in the survival and activation of normal B cells also.
Published: 2008

31. Combinatorial signalling controls Neurogenin2 expression at the onset of spinal neurogenesis

Author: François Guillemot, Isabelle Le Roux, Vanessa Ribes, Pascal Dollé, Laurent Bianchetti, Fanny Stutzmann, 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, Division of Molecular Neurobiology, National Institute for Medical Research (NIMR), Peney, Maité, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, Indoles, Oligonucleotides, Retinoic acid, Electrophoretic Mobility Shift Assay, Fibroblast growth factor, Shh, MESH: Spinal Cord, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Oligonucleotides, MESH: Basic Helix-Loop-Helix Transcription Factors, MESH: Gene Expression Regulation, Developmental, Basic Helix-Loop-Helix Transcription Factors, FGF, MESH: Animals, MESH: Nerve Tissue Proteins, Sonic hedgehog, In Situ Hybridization, MESH: Indoles, Genetics, 0303 health sciences, biology, Neurogenesis, Gene Expression Regulation, Developmental, Neurogenin2, Immunohistochemistry, Cell biology, Spinal Cord, embryonic structures, Neural plate, MESH: Fibroblast Growth Factors, Signal Transduction, Cell type, MESH: Mice, Transgenic, Promoter analysis, Mice, Transgenic, Nerve Tissue Proteins, Tretinoin, 03 medical and health sciences, MESH: In Situ Hybridization, Animals, Hedgehog Proteins, MESH: Galactosides, Enhancer, MESH: Mice, Molecular Biology, 030304 developmental biology, MESH: Tretinoin, Embryogenesis, MESH: Immunohistochemistry, Galactosides, MESH: Hedgehog Proteins, Cell Biology, [SDV.ETH] Life Sciences [q-bio]/Ethics, [SDV.ETH]Life Sciences [q-bio]/Ethics, Fibroblast Growth Factors, chemistry, MESH: Electrophoretic Mobility Shift Assay, biology.protein, RA, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; A central issue during embryonic development is to define how different signals cooperate in generating unique cell types. To address this issue, we focused on the function and the regulation of the proneural gene Neurogenin2 (Neurog2) during early mouse spinal neurogenesis. We showed that Neurog2 is first expressed in cells within the neural plate anterior to the node from the 5 somite-stage. The analysis of Neurog2 mutants established a role for this gene in triggering neural differentiation during spinal cord elongation. We identified a 798 base pair enhancer element (Neurog2-798) upstream of the Neurog2 coding sequence that directs the early caudal expression of Neurog2. Embryo culture experiments showed that Retinoic Acid (RA), Sonic hedgehog (Shh) and Fibroblast Growth Factor signals act in concert on this enhancer to control the spatial and temporal induction of Neurog2. We further demonstrated by transgenesis that two RA response elements and a Gli binding site within the Neurog2-798 element are absolutely required for its activity, strongly suggesting that the regulation of Neurog2 early expression by RA and Shh signals is direct. Our data thus support a model where signal integration at the level of a single enhancer constitutes a key mechanism to control the onset of neurogenesis.
Published: 2008

32. Efficient and specific transduction of cochlear supporting cells by adeno-associated virus serotype 5

Author: Xavier Estivill, Frédéric Venail, Maria L. Arbonés, Ester Ballana, Jing Wang, Assumpció Bosch, Jean-Luc Puel, Genes and Disease Program, Centre de Regulacio´ Geno´mica-CRG-UPF, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Biomedical Research on Epidemiology and Public Health, CIBER de Epidemiología y Salud Pública (CIBERESP), Centre for Biomedical Research on Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Department of Biochemistry and Molecular Biology, Centre of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona (UAB), and Hamel, Christian
Subjects: Calbindins, Receptor, Platelet-Derived Growth Factor alpha, Phalloidine, MESH: Receptor, Platelet-Derived Growth Factor alpha, Genetic enhancement, MESH: Membrane Glycoproteins, Peripherins, Gene Expression, MESH: Intermediate Filament Proteins, MESH: Dependovirus, medicine.disease_cause, Connexins, MESH: Animals, Newborn, Mice, Transduction (genetics), 0302 clinical medicine, Intermediate Filament Proteins, Neurofilament Proteins, Transduction, Genetic, MESH: Genetic Vectors, MESH: Cochlea, MESH: Glial Fibrillary Acidic Protein, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Neurofilament Proteins, Adeno-associated virus, 0303 health sciences, Membrane Glycoproteins, General Neuroscience, Genetic transfer, Peripherin, Dependovirus, MESH: Transduction, Genetic, Cochlea, Connexin 26, medicine.anatomical_structure, Myosin VIIa, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Phalloidine, MESH: Gene Expression, Genetic Vectors, Green Fluorescent Proteins, Guinea Pigs, Nerve Tissue Proteins, Myosins, Biology, MESH: Hair Cells, Auditory, Inner, MESH: Guinea Pigs, 03 medical and health sciences, Organ Culture Techniques, S100 Calcium Binding Protein G, MESH: Green Fluorescent Proteins, Glial Fibrillary Acidic Protein, otorhinolaryngologic diseases, medicine, Animals, Inner ear, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, Tropism, MESH: Myelin Basic Proteins, 030304 developmental biology, Hair Cells, Auditory, Inner, MESH: Calcium-Binding Protein, Vitamin D-Dependent, Myelin Basic Protein, MESH: Myosins, MESH: Organ Culture Techniques, MESH: Connexins, Animals, Newborn, Immunology, sense organs, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Congenital deafness, affecting 1 in 1000 neonates, can lead to major problems in speech, cognitive and psychosocial development. Congenital deafness is mainly caused by mutations in connexins, hemi-channel proteins forming gap-junctions between supporting cells in the sensory epithelia. We describe a high tropism of AAV5 serotype for the supporting cells of the cochlea, both in vitro in postnatal day 4 mouse explants, and in vivo in the adult guinea-pig inner ear, through scala media perfusion. AAV5 transduction correlates with PDGFRalpha expression, previously reported as AAV5 receptor. This vector could be of major interest in addressing gene therapy approaches to deafness as well as for studying basic aspects of inner-ear development and hearing mechanisms.
Published: 2008

33. Protein degradation, as with protein synthesis, is required during not only long-term spatial memory consolidation but also reconsolidation

Author: Lionel Moulédous, Julien Artinian, Xavier De Jaeger, Pascal Roullet, Bernard Frances, Anne-Marie T. McGauran, Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-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)-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), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Male, MESH: Hippocampus, Long-Term Potentiation, MESH: Neurons, Morris water navigation task, Hippocampal formation, Hippocampus, Mice, chemistry.chemical_compound, 0302 clinical medicine, Protein biosynthesis, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Memory, Anisomycin, Neurons, Protein Synthesis Inhibitors, 0303 health sciences, Consolidation (soil), General Neuroscience, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Memory consolidation, Psychology, MESH: Space Perception, Lactacystin, MESH: Anisomycin, Nerve Tissue Proteins, Cysteine Proteinase Inhibitors, Protein degradation, MESH: Cysteine Proteinase Inhibitors, 03 medical and health sciences, MESH: Acetylcysteine, MESH: Long-Term Potentiation, Memory, Animals, Maze Learning, MESH: Mice, 030304 developmental biology, Communication, MESH: Protein Synthesis Inhibitors, business.industry, MESH: Maze Learning, MESH: Male, Acetylcysteine, chemistry, Space Perception, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: The formation of long-term memory requires protein synthesis, particularly during initial memory consolidation. This process also seems to be dependant upon protein degradation, particularly degradation by the ubiquitin-proteasome system. The aim of this study was to investigate the temporal requirement of protein synthesis and degradation during the initial consolidation of allocentric spatial learning. As memory returns to a labile state during reactivation, we also focus on the role of protein synthesis and degradation during memory reconsolidation of this spatial learning. Male CD1 mice were submitted to massed training in the spatial version of the Morris water maze. At various time intervals after initial acquisition or after a reactivation trial taking place 24 h after acquisition, mice received an injection of either the protein synthesis inhibitor anisomycin or the protein degradation inhibitor lactacystin. This injection was performed into the hippocampal CA3 region, which is specifically implicated in the processing of spatial information. Results show that, in the CA3 hippocampal region, consolidation of an allocentric spatial learning task requires two waves of protein synthesis taking place immediately and 4 h after acquisition, whereas reconsolidation requires only the first wave. However, for protein degradation, both consolidation and reconsolidation require only one wave, taking place immediately after acquisition or reactivation, respectively. These findings suggest that protein degradation is a key step for memory reconsolidation, as for consolidation. Moreover, as protein synthesis-dependent reconsolidation occurred faster than consolidation, reconsolidation did not consist of a simple repetition of the initial consolidation.
Published: 2008

34. MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary

Author: Christoph Leucht, Anja Folchert, Laure Bally-Cuif, Andrea Wizenmann, Ruth Klafke, Christian Stigloher, Department of Zebrafish Neurogenetics, Institute of Developmental Genetics, German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Department of Zebrafish Neurogenetics, Helmholtz Zentrum München, Helmholtz-Zentrum München (HZM), and Institute of Stem Cell Research
Subjects: MESH: Signal Transduction, MESH: Zebrafish Proteins, Hindbrain, MESH: Dose-Response Relationship, Drug, Neuroscientist, MESH: Animals, Genetically Modified, Midbrain, 03 medical and health sciences, 0302 clinical medicine, MESH: Promoter Regions, Genetic, MESH: Gene Expression Regulation, Developmental, medicine, MESH: Animals, MESH: Organizers, Embryonic, MESH: Nerve Tissue Proteins, Progenitor cell, MESH: Zebrafish, Zebrafish, MESH: Numerical Analysis, Computer-Assisted, 030304 developmental biology, Progenitor, 0303 health sciences, biology, General Neuroscience, Neurogenesis, Neural tube, MESH: Embryo, Nonmammalian, MESH: Rhombencephalon, MESH: Mesencephalon, biology.organism_classification, medicine.anatomical_structure, nervous system, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: MicroRNAs, Neuroscience, MESH: Fibroblast Growth Factors, 030217 neurology & neurosurgery, MESH: Body Patterning
Abstract: International audience; The midbrain-hindbrain boundary (MHB) is a long-lasting organizing center in the vertebrate neural tube that is both necessary and sufficient for the ordered development of midbrain and anterior hindbrain (midbrain-hindbrain domain, MH). The MHB also coincides with a pool of progenitor cells that contributes neurons to the entire MH. Here we show that the organizing activity and progenitor state of the MHB are co-regulated by a single microRNA, miR-9, during late embryonic development in zebrafish. Endogenous miR-9 expression, initiated at late stages, selectively spares the MHB. Gain- and loss-of-function studies, in silico predictions and sensor assays in vivo demonstrate that miR-9 targets several components of the Fgf signaling pathway, thereby delimiting the organizing activity of the MHB. In addition, miR-9 promotes progression of neurogenesis in the MH, defining the MHB progenitor pool. Together, these findings highlight a previously unknown mechanism by which a single microRNA fine-tunes late MHB coherence via its co-regulation of patterning activities and neurogenesis.
Published: 2008

35. Processing and Nuclear Localization of CRMP2 during Brain Development Induce Neurite Outgrowth Inhibition

Author: Mahnaz Moradi-Améli, Carole Auger, Jérôme Honnorat, Véronique Rogemond, Nathalie Auvergnon, Marie-Françoise Belin, Pascale Giraudon, Michel Becchi, Neuro-oncologie et neuro-inflammation, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie B, Hospices Civils de Lyon (HCL), IFR des neurosciences de Lyon (IFNL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Centre Hospitalier le Vinatier [Bron]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie expérimentale et physiopathologie, Université de Lyon-Université de Lyon-IFR19-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 Rogemond, Véronique
Subjects: Male, MESH: Cell Differentiation, MESH: Rats, Neurite, Cellular differentiation, Molecular Sequence Data, Active Transport, Cell Nucleus, MESH: Sequence Alignment, Nerve Tissue Proteins, MESH: Active Transport, Cell Nucleus, MESH: Amino Acid Sequence, MESH: Protein Isoforms, Biology, Biochemistry, MESH: Protein Structure, Tertiary, MESH: Brain, MESH: Gene Expression Regulation, Developmental, Neurites, medicine, Animals, Protein Isoforms, MESH: Animals, Amino Acid Sequence, MESH: Nerve Tissue Proteins, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Growth cone, Cytoskeleton, Molecular Biology, MESH: Molecular Sequence Data, MESH: Receptor, EphA5, Brain, Gene Expression Regulation, Developmental, Receptor, EphA5, Cell Differentiation, Cell Biology, MESH: Neurites, MESH: Male, Protein Structure, Tertiary, Rats, Cell biology, Cell nucleus, medicine.anatomical_structure, Cytoplasm, Intercellular Signaling Peptides and Proteins, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Collapsin response mediator protein family, Sequence Alignment, Nuclear localization sequence
Abstract: International audience; Collapsin response mediator proteins (CRMPs) are believed to play a crucial role in neuronal differentiation and axonal outgrowth. Among them, CRMP2 mediates axonal guidance by collapsing growth cones during development. This activity is correlated with the reorganization of cytoskeletal proteins. CRMP2 is implicated in the regulation of several intracellular signaling pathways. Two subtypes, A and B, and multiple cytosolic isoforms of CRMP2B with apparent masses between 62 and 66 kDa have previously been reported. Here, we show a new short isoform of 58 kDa, expressed during brain development, derived from C-terminal processing of the CRMP2B subtype. Although full-length CRMP2 is restricted to the cytoplasm, using transfection experiments, we demonstrate that a part of the short isoform is found in the nucleus. Interestingly, at the tissue level, this short CRMP2 is also found in a nuclear fraction of brain extract. By mutational analysis, we demonstrate, for the first time, that nuclear translocation occurs via nuclear localization signal (NLS) within residues Arg(471)-Lys(472) in CRMP2 sequence. The NLS may be unmasked after C-terminal processing; thereby, this motif may be surface-exposed. This short CRMP2 induces neurite outgrowth inhibition in neuroblastoma cells and suppressed axonal growth in cultured cortical neurons, whereas full-length CRMP2 promotes neurite elongation. The NLS-mutated short isoform, restricted to the cytoplasm, abrogates both neurite outgrowth and axon growth inhibition, indicating that short nuclear CRMP2 acts as a dominant signal. Therefore, post-transcriptional processing of CRMP2 together with its nuclear localization may be an important key in the regulation of neurite outgrowth in brain development.
Published: 2008

36. In Vitro and in Cellulo Evidences for Association of the Survival of Motor Neuron Complex with the Fragile X Mental Retardation Protein

Author: Séverine Massenet, Hervé Moine, Florence Rage, Christiane Branlant, Nathalie Piazzon, Florence Schlotter, 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, Maturation des ARN et enzymologie moléculaire (MAEM), Cancéropôle du Grand Est-Université Henri Poincaré - Nancy 1 (UHP)-IFR111-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and MASSENET, Séverine
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], animal diseases, Biochemistry, Fragile X Mental Retardation Protein, Mice, MESH: Protein Structure, Tertiary, 0302 clinical medicine, SMN complex, MESH: Muscular Atrophy, Spinal, Translational regulation, MESH: Animals, MESH: Nerve Tissue Proteins, Cyclic AMP Response Element-Binding Protein, Motor Neurons, 0303 health sciences, RNA-Binding Proteins, SMN Complex Proteins, Exons, Cell biology, medicine.anatomical_structure, MESH: Fragile X Syndrome, MESH: Motor Neurons, MESH: Cyclic AMP Response Element-Binding Protein, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Cell Line, Tumor, Immunoprecipitation, Recombinant Fusion Proteins, Hypothalamus, Nerve Tissue Proteins, Biology, MESH: Fragile X Mental Retardation Protein, Muscular Atrophy, Spinal, 03 medical and health sciences, Cell Line, Tumor, MESH: Recombinant Fusion Proteins, medicine, Animals, Humans, MRNA transport, MESH: Mice, Molecular Biology, 030304 developmental biology, MESH: Humans, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Survival of motor neuron, Cell Biology, Spinal muscular atrophy, Motor neuron, medicine.disease, Survival of Motor Neuron 1 Protein, MESH: Hypothalamus, Molecular biology, Protein Structure, Tertiary, nervous system diseases, MESH: RNA-Binding Proteins, nervous system, Fragile X Syndrome, MESH: Exons, 030217 neurology & neurosurgery
Abstract: International audience; Spinal muscular atrophy (SMA) is caused by reduced levels of the survival of motor neuron (SMN) protein. Although the SMN complex is essential for assembly of spliceosomal U small nuclear RNPs, it is still not understood why reduced levels of the SMN protein specifically cause motor neuron degeneration. SMN was recently proposed to have specific functions in mRNA transport and translation regulation in neuronal processes. The defective protein in Fragile X mental retardation syndrome (FMRP) also plays a role in transport of mRNPs and in their translation. Therefore, we examined possible relationships of SMN with FMRP. We observed granules containing both transiently expressed red fluorescent protein(RFP)-tagged SMN and green fluorescent protein(GFP)-tagged FMRP in cell bodies and processes of rat primary neurons of hypothalamus in culture. By immunoprecipitation experiments, we detected an association of FMRP with the SMN complex in human neuroblastoma SH-SY5Y cells and in murine motor neuron MN-1 cells. Then, by in vitro experiments, we demonstrated that the SMN protein is essential for this association. We showed that the COOH-terminal region of FMRP, as well as the conserved YG box and the region encoded by exon 7 of SMN, are required for the interaction. Our findings suggest a link between the SMN complex and FMRP in neuronal cells.
Published: 2008

37. Birth after pre-implantation genetic diagnosis (PGD) of spinocerebellar ataxia 2 (Sca2)

Author: Jean-Christophe Nicod, Céline Moutou, Nathalie Gardes, Stéphane Viville, 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 Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I
Subjects: Adult, Male, medicine.medical_specialty, Pathology, MESH: Spinocerebellar Ataxias, MESH: Pedigree, Nerve Tissue Proteins, Biology, Polymerase Chain Reaction, Andrology, 03 medical and health sciences, MESH: Pregnancy, 0302 clinical medicine, Pregnancy, Genotype, Multiplex polymerase chain reaction, medicine, Humans, Spinocerebellar Ataxias, MESH: Preimplantation Diagnosis, Sperm Injections, Intracytoplasmic, MESH: Nerve Tissue Proteins, Neonatology, Allele, Preimplantation Diagnosis, Genetics (clinical), Twin Pregnancy, 030304 developmental biology, 0303 health sciences, MESH: Humans, 030219 obstetrics & reproductive medicine, Obstetrics and Gynecology, MESH: Adult, MESH: Polymerase Chain Reaction, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, Pedigree, 3. Good health, Ataxins, Spinocerebellar ataxia, Microsatellite, Female, MESH: Microsatellite Repeats, MESH: Female, Microsatellite Repeats, MESH: Sperm Injections, Intracytoplasmic
Abstract: Background Spinocerebellar ataxia 2 (SCA2) is an autosomal-dominant neurodegenerative disease caused by an extended polyglutamine sequence in the ATXN2 protein. We describe the development of a new single-cell multiplex PCR protocol for pre-implantation genetic diagnosis (PGD) of SCA2 and its successful clinical application. Methods Three duplex tests have been developed, one, which combines the detection of the CAG repeats in addition to the D12S821 microsatellite, another, the amplification of the CAG repeats and the D12S1333 microsatellite and the last, the combination of both microsatellites D12S821 and D12S1333. Results PCR conditions were established using 226 single lymphoblasts or patient lymphocysts. Amplification was obtained in an average of 99.6%, a complete genotype in 86%, a conclusive result in 96% and an allelic drop-out (ADO) rate of 10.7% was observed. PGD for SCA2 was performed for a couple with a paternal risk of transmitting the pathology. Two cycles were done from which 18 embryos were biopsied, 8 were diagnosed as unaffected, 9 as affected and 1 gave no results. In both cycles 2 embryos were transferred, with no pregnancy at the first attempt, and a twin pregnancy at the second attempt. The patient delivered one girl and one boy at 36 weeks and 3 days. Copyright © 2008 John Wiley & Sons, Ltd.
Published: 2008

38. The TASK background K2P channels: chemo- and nutrient sensors

Author: Eric Honoré, Fabrice Duprat, Amanda Patel, Inger Lauritzen, 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), and ANR 2005 Cardiovasculaire-obésité-diabète, Association for Information and Research on Genetic Kidney Disease France, Fondation del Duca, Fondation de France, Fondation de la Recherche Médicale, EEC Marie-Curie fellowships, Fondation de Recherche sur l'Hypertension Artérielle, AFM, HFSP,INSERM and CNRS
Subjects: MESH: Signal Transduction, MESH: Neurons, Nerve Tissue Proteins, Stimulation, Models, Biological, 03 medical and health sciences, Potassium Channels, Tandem Pore Domain, 0302 clinical medicine, Glomus cell, medicine, Animals, Humans, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Chemoreceptors, 030304 developmental biology, Acidosis, Neurons, 0303 health sciences, MESH: Humans, Chemistry, General Neuroscience, MESH: Models, Biological, MESH: Potassium Channels, Tandem Pore Domain, MESH: Ion Channel Gating, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Chemoreceptor Cells, 3. Good health, Orexin, Oxygen, MESH: Glucose, Electrophysiology, Glucose, medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Carotid body, Neuron, Brainstem, medicine.symptom, Ion Channel Gating, Neuroscience, MESH: Oxygen, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Signal Transduction
Abstract: Specialized chemo- and nutrient-sensing cells share a common electrophysiological mechanism by transducing low O(2), high CO(2) and low glucose stimuli into a compensatory cellular response: the closing of background K(+) channels encoded by the K(2P) subunits. Inhibition of the TASK K(2P) channels by extracellular acidosis leads to an increased excitability of brainstem respiratory neurons. Moreover, hypoxic down-modulation of TASK channels is implicated in the activation of glomus cells in the carotid body. Stimulation of both types of cell leads to an enhanced ventilation and to cardiocirculatory adjustments. Differential modulation of TASK channels by acidosis and high glucose alters excitability of the hypothalamic orexin neurons, which influence arousal, food seeking and breathing. These recent results shed light on the role of TASK channels in sensing physiological stimuli.
Published: 2007

39. Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?

Author: Alain Destée, Alexis Brice, Nawal Benammar, Alexandra Durr, François Sellal, A. M. Bonnet, P. Charles, Giovanni Stevanin, Suzanne Lesage, I. Le Ber, Agnès Camuzat, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Clinique Neurologique, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), ANR, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, MESH: DNA Repeat Expansion, MESH: Risk Assessment, 0302 clinical medicine, Degenerative disease, Autosomal dominant cerebellar ataxia, Risk Factors, MESH: Risk Factors, Prevalence, MESH: Nerve Tissue Proteins, MESH: Heterozygote, MESH: Aged, Genetics, 0303 health sciences, DNA Repeat Expansion, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, Parkinsonism, MESH: Genetic Predisposition to Disease, Parkinson Disease, Middle Aged, LRRK2, Phenotype, Pedigree, Ataxins, Spinocerebellar ataxia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, medicine.symptom, Heterozygote, MESH: Pedigree, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, MESH: Prevalence, Aged, Repetitive Sequences, Nucleic Acid, 030304 developmental biology, MESH: Repetitive Sequences, Nucleic Acid, MESH: Humans, Cerebellar ataxia, medicine.disease, MESH: Male, nervous system diseases, MESH: France, Neurology (clinical), Trinucleotide repeat expansion, MESH: Female, MESH: Parkinson Disease, 030217 neurology & neurosurgery
Abstract: Background: Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2.Methods: We screened 164 families with ADP for expansions in the SCA2, 3, and 17 genes and for the G2019S mutation in LRRK2. The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2, LRRK2, and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size.Results: Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2. In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs.Conclusion: These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.
Published: 2007

40. A novel cell response triggered by interphase centromere structural instability

Author: Eric Morency, Mirna Sabra, Patrick Lomonte, Frédéric Catez, Pascale Texier, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: Chromosomal Proteins, Non-Histone, Herpesvirus 1, Human, MESH: DNA Breaks, Mice, MESH: Animals, MESH: Nerve Tissue Proteins, Cyclic AMP Response Element-Binding Protein, Kinetochores, Research Articles, Cells, Cultured, 0303 health sciences, Kinetochore, 030302 biochemistry & molecular biology, Nuclear Proteins, RNA-Binding Proteins, SMN Complex Proteins, MESH: DNA, Satellite, Cell biology, MESH: Herpesvirus 1, Human, MESH: Centromere, RNA Interference, Coilin, Interphase, MESH: Centromere Protein B, MESH: Cells, Cultured, MESH: Cyclic AMP Response Element-Binding Protein, Ubiquitin-Protein Ligases, MESH: RNA Interference, Centromere, Centromere protein B, Nerve Tissue Proteins, DNA, Satellite, Biology, Article, Immediate early protein, Immediate-Early Proteins, MESH: Interphase, 03 medical and health sciences, MESH: Chromosomal Proteins, Non-Histone, Microtubule, Animals, Humans, MESH: Mice, Mitosis, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Kinetochores, DNA Breaks, MESH: Immediate-Early Proteins, Cell Biology, MESH: Ubiquitin-Protein Ligases, MESH: RNA-Binding Proteins, MESH: Nuclear Proteins, Centromere Protein B
Abstract: International audience; Interphase centromeres are crucial domains for the proper assembly of kinetochores at the onset of mitosis. However, it is not known whether the centromere structure is under tight control during interphase. This study uses the peculiar property of the infected cell protein 0 of herpes simplex virus type 1 to induce centromeric structural damage, revealing a novel cell response triggered by centromere destabilization. It involves centromeric accumulation of the Cajal body-associated coilin and fibrillarin as well as the survival motor neuron proteins. The response, which we have termed interphase centromere damage response (iCDR), was observed in all tested human and mouse cells, indicative of a conserved mechanism. Knockdown cells for several constitutive centromere proteins have shown that the loss of centromeric protein B provokes the centromeric accumulation of coilin. We propose that the iCDR is part of a novel safeguard mechanism that is dedicated to maintaining interphase centromeres compatible with the correct assembly of kinetochores, microtubule binding, and completion of mitosis.
Published: 2007

41. Robo1 and Robo2 Cooperate to Control the Guidance of Major Axonal Tracts in the Mammalian Forebrain

Author: Marc Tessier-Lavigne, Coralie Fouquet, Guillermina López-Bendito, Nuria Flames, Thomas Di Meglio, Oscar Marín, Alain Chédotal, Le Ma, Instituto de Neurociencias de Alicante, Universidad Miguel Hernández [Elche] (UMH)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Howard Hughes Medical Institute (HHMI), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), and Genentech, Inc. [San Francisco]
Subjects: Nervous system, Midline, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, Guidepost cells, Mice, 0302 clinical medicine, Thalamus, Thalamocortical, SLIT1, MESH: Animals, MESH: Nerve Tissue Proteins, Receptors, Immunologic, Axon, In Situ Hybridization, Cerebral Cortex, MESH: Thalamus, 0303 health sciences, Axon guidance, General Neuroscience, Articles, Immunohistochemistry, Slit, 3. Good health, medicine.anatomical_structure, Cortex, Intercellular Signaling Peptides and Proteins, MESH: Axons, MESH: Gene Expression, MESH: Mutation, Nerve Tissue Proteins, Robo, Biology, 03 medical and health sciences, MESH: In Situ Hybridization, ROBO1, medicine, Animals, RNA, Messenger, MESH: Intercellular Signaling Peptides and Proteins, MESH: Receptors, Immunologic, MESH: Mice, Repulsion, MESH: RNA, Messenger, 030304 developmental biology, MESH: Immunohistochemistry, Axons, MESH: Cerebral Cortex, nervous system, Mutation, Forebrain, Neuroscience, 030217 neurology & neurosurgery
Abstract: PMID:17392456, The function of the nervous system depends on the precision of axon wiring during development. Previous studies have demonstrated that Slits, a family of secreted chemorepellent proteins, are crucial for the proper development of several major forebrain tracts. Mice deficient in Slit2 or, even more so, in both Slit1 and Slit2 have defects in multiple axonal pathways, including corticofugal, thalamocortical, and callosal connections. In the spinal cord, members of the Robo family of proteins help mediate the function of Slits, but the relative contribution of these receptors to the guidance of forebrain projections remains to be determined. In the present study, we addressed the function of Robo1 and Robo2 in the guidance of forebrain projections by analyzing Robo1-, Robo2-, and Robo1;Robo2-deficient mice. Mice deficient in Robo2 and, more dramatically, in both Robo1 and Robo2, display prominent axon guidance errors in the development of corticofugal, thalamocortical, and corticocortical callosal connections. Our results demonstrate that Robo1 and Robo2 mostly cooperate to mediate the function of Slit proteins in guiding the major forebrain projections., This work was supported by grants from Spanish Government (BFU2005-04773/BMC) and the European Young Investigator (EURYI) program (O.M.) and from Association pour la Recherche sur le Cancer (A.C.).
Published: 2007

42. Differences in locomotor behavior revealed in mice deficient for the calcium-binding proteins parvalbumin, calbindin D-28k or both

Author: Alessandro E. P. Villa, Igor V. Tetko, Jan Eriksson, Patrick Gregory, Céline Mariethoz, Jaroslaw J. Barski, Maria A. Farré-Castany, Isabelle Schmutz, David P. Wolfer, Marco R. Celio, Beat Schwaller, Urs Albrecht, Unit of Anatomy, Albert-Ludwigs-Universität Freiburg, Neuroheuristic Research Group, ISI Foundation, AG Cellular Dynamics, Max Planck Institute of Neurobiology (MPIN), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Institute for Bioinformatics [Neuherberg], Helmholtz-Zentrum München (HZM), Institute of Anatomy, Universität Zürich [Zürich] = University of Zurich (UZH), Unit of Biochemistry, Neurosciences précliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Issartel, Jean-Paul
Subjects: Calbindins, MESH: Mice, Mutant Strains, Purkinje cell, MESH: Calcium-Binding Proteins, MESH: Rotarod Performance Test, MESH: Mice, Knockout, Calbindin, Mice, Behavioral Neuroscience, 0302 clinical medicine, Calcium-binding protein, MESH: Animals, MESH: Nerve Tissue Proteins, Mice, Knockout, 0303 health sciences, biology, musculoskeletal, neural, and ocular physiology, MESH: Motor Activity, Motor coordination, Parvalbumins, medicine.anatomical_structure, Peripheral nervous system, Knockout mouse, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, MESH: Exploratory Behavior, medicine.medical_specialty, Spatial Behavior, Nerve Tissue Proteins, Motor Activity, Rotarod performance test, 03 medical and health sciences, MESH: Parvalbumins, S100 Calcium Binding Protein G, MESH: Spatial Behavior, Internal medicine, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, 030304 developmental biology, Calcium-Binding Proteins, Mice, Mutant Strains, Endocrinology, Rotarod Performance Test, Exploratory Behavior, biology.protein, MESH: Female, 030217 neurology & neurosurgery, Parvalbumin
Abstract: We investigated the role of the two calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB) in the locomotor activity and motor coordination using null-mutant mice for PV (PV−/−), CB (CB−/−) or both proteins (PV−/−CB−/−). These proteins are expressed in distinct, mainly non-overlapping populations of neurons of the central and peripheral nervous system and PV additionally in fast-twitch muscles. In a test measuring repeated locomotor activity during 18–20 days, the analysis revealed a slightly increased activity in mice lacking either protein, while the lack of both decreased the number of beams crossed during active periods. An increase in the characteristic speed during the first 8 days could be attributed to PVdeficiency, while the elimination of CB in CB−/− and double-KO mice decreased the percentage of fast movements at all time points. In the latter, additionally a reduction of the fastest speed was observed. The alterations in locomotor activity (fast movements, fastest speed) strongly correlate with the impairment in locomotor coordination in mice deficient for CB evidenced in the runway assay and the rotarod assay. The graded locomotor phenotype (CB > PV) is qualitatively correlated with alterations in Purkinje cell firing reported previously in these mice. The presence or absence of either protein did not affect the spontaneous locomotor activity when animals were placed in a novel environment and tested only once for 30 min. In summary, the lack of these calcium-binding proteins yields characteristic, yet distinct phenotypes with respect to locomotor activity and coordination. © 2007 Elsevier B.V. All rights reserved.
Published: 2007

43. Distribution of Smoothened at hippocampal mossy fiber synapses

Author: Martial Ruat, Bernard, Christelle Masdeu, Hélène Faure, Elisabeth Traiffort, Institut de Neurobiologie Alfred Fessard (INAF), Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), 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), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), 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: Mossy fiber (hippocampus), Patched, G-protein-coupled receptor, hedgehog, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Membrane Glycoproteins, Nerve Tissue Proteins, MESH: Receptors, G-Protein-Coupled, Biology, Hippocampal formation, Receptors, G-Protein-Coupled, Mice, 03 medical and health sciences, 0302 clinical medicine, Microscopy, Electron, Transmission, synaptic vesicles, medicine, Animals, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], dentate gyrus, MESH: Nerve Tissue Proteins, patched, MESH: Mice, 030304 developmental biology, Hippocampal mossy fiber, 0303 health sciences, Membrane Glycoproteins, General Neuroscience, Dentate gyrus, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Mossy Fibers, Hippocampal, Granule cell, Smoothened Receptor, bouton, medicine.anatomical_structure, MESH: Subcellular Fractions, Mossy Fibers, Hippocampal, MESH: Microscopy, Electron, Transmission, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Smoothened, Neuroscience, 030217 neurology & neurosurgery, Subcellular Fractions, MESH: Dentate Gyrus
Abstract: The seven-transmembrane receptor Smoothened is essential for hedgehog signal transduction. In adulthood, the highest density of Smoothened mRNA is found in the granule cell layer of the dentate gyrus. There, Smoothened expression is regulated by the synaptic activity involving the glutamatergic transmission. The precise localization of Smoothened proteins, however, has not yet been reported. Here, we describe Smoothened protein distribution in the hippocampal mossy fibers using specific Smoothened antibodies. We provide evidences for their presynaptic localization, and using electron microscopy, show that Smoothened is located in close association with synaptic vesicles and rarely with the plasma membrane. These findings demonstrate that Smoothened is localized presynaptically and suggest that Smoothened signal transduction may be implicated in the complex aspects of mossy fiber function.
Published: 2007

44. Neurogenic role of Gcm transcription factors is conserved in chicken spinal cord

Author: Philippe Cochard, Laurent Soustelle, Cécile Jacques, Françoise Trousse, Cathy Soula, Julián Cerón, Angela Giangrande, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Drosophila, MESH: Neurons, Genes, Insect, Chick Embryo, MESH: Genes, Insect, Animals, Genetically Modified, MESH: Recombinant Proteins, MESH: Spinal Cord, Mice, 0302 clinical medicine, MESH: Gene Expression Regulation, Developmental, Drosophila Proteins, MESH: Animals, MESH: Nerve Tissue Proteins, Neurons, 0303 health sciences, Gene Expression Regulation, Developmental, Cell Differentiation, Embryo, MESH: Transcription Factors, Anatomy, MESH: Chick Embryo, Cell cycle, Recombinant Proteins, Cell biology, DNA-Binding Proteins, medicine.anatomical_structure, Spinal Cord, Drosophila, MESH: Neuroglia, Neuroglia, MESH: Cell Differentiation, MESH: Drosophila Proteins, Central nervous system, Nerve Tissue Proteins, Biology, Transfection, MESH: Animals, Genetically Modified, 03 medical and health sciences, medicine, Animals, Humans, Progenitor cell, MESH: Mice, Molecular Biology, Gene, Transcription factor, 030304 developmental biology, Progenitor, MESH: Humans, MESH: Transfection, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Spinal cord, MESH: Hela Cells, MESH: DNA-Binding Proteins, 030217 neurology & neurosurgery, HeLa Cells, Transcription Factors, Developmental Biology
Abstract: Although glial cells missing (gcm) genes are known as glial determinants in the fly embryo, the role of vertebrate orthologs in the central nervous system is still under debate. Here we show for the first time that the chicken ortholog of fly gcm (herein referred to as c-Gcm1), is expressed in early neuronal lineages of the developing spinal cord and is required for neural progenitors to differentiate as neurons. Moreover, c-Gcm1 overexpression is sufficient to trigger cell cycle exit and neuronal differentiation in neural progenitors. Thus, c-Gcm1 expression constitutes a crucial step in the developmental cascade that prompts progenitors to generate neurons: c-Gcm1 acts downstream of proneural (neurogenin) and progenitor (Sox1-3) factors and upstream of NeuroM neuronal differentiation factor. Strikingly, this neurogenic role is not specific to the vertebrate gene, as fly gcmand gcm2 are also sufficient to induce the expression of neuronal markers. Interestingly, the neurogenic role is restricted to post-embryonic stages and we identify two novel brain neuronal lineages expressing and requiring gcm genes. Finally, we show that fly gcm and the chick and mouse orthologs induce expression of neural markers in HeLa cells. These data, which demonstrate a conserved neurogenic role for Gcm transcription factors, call for a re-evaluation of the mode of action of these genes during evolution.
Published: 2007

45. Gray platelet syndrome can mimic autoimmune lymphoproliferative syndrome

Author: Ehl, Anne, Pannicke, Ulrich, Zimmermann, Stefanie-Yvonne, Lorenz, R., Neven, Benedicte, Fuchs, Ilka, Salzer, Ulrich, Speckmann, Carsten, Strauss, Anne, Maass, E., Collet, Benedicte, Enders, Anselm, Favier, Remi, Alessi, Marie-Christine, Rieux-Laucat, Frederic, Zieger, Barbara, Schwarz, Klaus, Ehl, Stephan, Lorenz, Myriam Ricarda, Maaβ, Eberhard, Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ALESSI, Marie-Christine
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Somatic cell, Immunology, Fas Ligand Protein, Disease, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biochemistry, Germline, Gray platelet syndrome, MESH: Autoimmune Lymphoproliferative Syndrome, MESH: Gray Platelet Syndrome, Correspondence, medicine, MESH: Blood Proteins, MESH: Nerve Tissue Proteins, ComputingMilieux_MISCELLANEOUS, MESH: Receptors, Cell Surface, MESH: Humans, business.industry, Autoimmune Cytopenia, MESH: Child, Preschool, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, medicine.disease, MESH: Infant, MESH: Male, MESH: Fas Ligand Protein, MESH: Antigens, CD95, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autoimmune lymphoproliferative syndrome, business, MESH: Female
Abstract: To the editor: The combination of splenomegaly and autoimmune cytopenia is frequently associated with primary immunodeficiencies. The most frequent disease is autoimmune lymphoproliferative syndrome (ALPS), caused by autosomal dominant germline or somatic mutations of the FAS gene.[1][1],[2][2] The
Published: 2015

46. Huntingtin proteolysis releases non‐polyQ fragments that cause toxicity through dynamin 1 dysregulation

Author: Marie‐Thérèse El‐Daher, Sandrine Lévêque-Fort, Juan Botas, Ismael Al-Ramahi, Emilie Hangen, Ghislaine Poizat, Raul Pardo, Julie Bruyère, Sandrine Humbert, Nicolas Bourg, Sylvie Souquere, Gérard Pierron, Frédéric Saudou, Céline Mayet, Signalisation cellulaire et neurobiologie (SNC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular and Human Genetics (Baylor College of Medicine), Baylor College of Medecine, Institut des Sciences Moléculaires d'Orsay (ISMO), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Rétrovirus endogènes et éléments rétroides des eucaryotes supérieurs (REERES (UMR 8122)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), and PERIGNON, Alain
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Huntingtin, MESH: Drosophila Proteins, Proteolysis, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mutant, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Huntingtin Protein, MESH: Proteolysis, Biology, Cleavage (embryo), General Biochemistry, Genetics and Molecular Biology, MESH: Drosophila melanogaster, MESH: Dynamin I, Huntington's disease, ER dilation, MESH: Endoplasmic Reticulum, MESH: Endoplasmic Reticulum Stress, mental disorders, medicine, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Serotonin Plasma Membrane Transport Proteins, Molecular Biology, MESH: Mice, Dynamin, MESH: Humans, General Immunology and Microbiology, medicine.diagnostic_test, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Peptides, General Neuroscience, Endoplasmic reticulum, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, TEV proteolysis, medicine.disease, MESH: Huntington Disease, Cell biology, nervous system diseases, endoplasmic reticulum, MESH: Microtubule-Associated Proteins, Biochemistry, Unfolded protein response, Drosophila, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences
Abstract: International audience; Cleavage of mutant huntingtin (HTT) is an essential process in Huntington's disease (HD), an inherited neurodegenerative disorder. Cleavage generates N-ter fragments that contain the polyQ stretch and whose nuclear toxicity is well established. However, the functional defects induced by cleavage of full-length HTT remain elusive. Moreover, the contribution of non-polyQ C-terminal fragments is unknown. Using time- and site-specific control of full-length HTT proteolysis, we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies. Surprisingly, in addition to the canonical pathogenic N-ter fragments, the C-ter fragments generated, that do not contain the polyQ stretch, induced toxicity via dilation of the endoplasmic reticulum (ER) and increased ER stress. C-ter HTT bound to dynamin 1 and subsequently impaired its activity at ER membranes. Our findings support a role for HTT on dynamin 1 function and ER homoeostasis. Proteolysis-induced alteration of this function may be relevant to disease.
Published: 2015

47. Integration of New Information with Active Memory Accounts for Retrograde Amnesia: A Challenge to the Consolidation/Reconsolidation Hypothesis?

Author: Joseph F. Lynch, Daniel Toledano, Aaron M. Jasnow, Pascale Gisquet-Verrier, Adam Richard Ulmen, David C. Riccio, Pasquale Cutolo, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), and Kent State University
Subjects: Male, MESH: Rats, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Amnesia, Retrograde, Amnesia, Nerve Tissue Proteins, MESH: Cognition, MESH: Rats, Sprague-Dawley, 050105 experimental psychology, Rats, Sprague-Dawley, 03 medical and health sciences, MESH: Brain, Cognition, 0302 clinical medicine, Memory, Active memory, MESH: Rats, Long-Evans, medicine, Animals, Rats, Long-Evans, 0501 psychology and cognitive sciences, MESH: Animals, MESH: Memory, MESH: Nerve Tissue Proteins, Memory recovery, Consolidation (soil), [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, General Neuroscience, 05 social sciences, Brain, Retention, Psychology, Retrograde amnesia, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Articles, medicine.disease, MESH: Male, Rats, MESH: Retention (Psychology), Taste aversion, Amnesia, Retrograde, Memory consolidation, medicine.symptom, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract: Active (new and reactivated) memories are considered to be labile and sensitive to treatments disrupting the time-dependent consolidation/reconsolidation processes required for their stabilization. Active memories also allow the integration of new information for updating memories. Here, we investigate the possibility that, when active, the internal state provided by amnesic treatments is represented and integrated within the initial memory and that amnesia results from the absence of this state at testing. We showed in rats that the amnesia resulting from systemic, intracerebroventricular and intrahippocampal injections of the protein synthesis inhibitor cycloheximide, administered after inhibitory avoidance training or reactivation, can be reversed by a reminder, including re-administration of the same drug. Similar results were obtained with lithium chloride (LiCl), which does not affect protein synthesis, when delivered systemically after training or reactivation. However, LiCl can induce memory given that a conditioned taste aversion was obtained for a novel taste, presented just before conditioning or reactivation. These results indicate that memories can be established and maintained without de novo protein synthesis and that experimental amnesia may not result from a disruption of memory consolidation/reconsolidation. The findings more likely support the integration hypothesis: posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval. This integration concept includes most of the previous explanations of memory recovery after retrograde amnesia and critically challenges the traditional memory consolidation/reconsolidation hypothesis, providing a more dynamic and flexible view of memory. SIGNIFICANCE STATEMENT This study provides evidence challenging the traditional consolidation/reconsolidation hypotheses that have dominated the literature over the past 50 years. Based on amnesia studies, that hypothesis states that active (i.e., new and reactivated) memories are similarly labile and (re)established in a time-dependent manner within the brain through processes that require de novo protein synthesis. Our data show that new/reactivated memories can be formed without protein synthesis and that amnesia can be induced by drugs that do not affect protein synthesis. We propose that amnesia results from memory integration of the internal state produced by the drug that is subsequently necessary for retrieval of the memory. This interpretation gives a dynamic view of memory, rapidly stored and easily updated when active.
Published: 2015

48. Directional Notch trafficking in Sara endosomes during asymmetric cell division in the spinal cord

Author: Sabine Kressmann, Marcos González-Gaitán, Maximilian Fürthauer, Claudia Guimarães Camargo Campos, Irinka Castanon, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: MESH: Neural Stem Cells, MESH: Signal Transduction, Embryo, Nonmammalian, Cell division, Cellular differentiation, MESH: Neurons, MESH: Spinal Cord, 0302 clinical medicine, Neural Stem Cells, Cell Movement, MESH: Gene Expression Regulation, Developmental, Asymmetric cell division, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Cell Movement, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Zebrafish, Neurons, 0303 health sciences, Receptors, Notch, Neurogenesis, Gene Expression Regulation, Developmental, Cell Differentiation, Neural stem cell, Endocytosis, Cell biology, Protein Transport, Spinal Cord, ddc:540, MESH: Endocytosis, Signal Transduction, MESH: Cell Differentiation, MESH: Protein Transport, Endosome, MESH: Asymmetric Cell Division, Nerve Tissue Proteins, MESH: Zebrafish Proteins, MESH: Carrier Proteins, Endosomes, Biology, Cell fate determination, 03 medical and health sciences, Animals, Cell Lineage, MESH: Zebrafish, Mitosis, 030304 developmental biology, Asymmetric Cell Division, MESH: Embryo, Nonmammalian, Cell Biology, Zebrafish Proteins, MESH: Cell Lineage, MESH: Neurogenesis, MESH: Endosomes, Carrier Proteins, MESH: Receptors, Notch, 030217 neurology & neurosurgery
Abstract: International audience; Asymmetric division of neural precursor cells contributes to the generation of a variety of neuronal types. Asymmetric division is mediated by the asymmetric inheritance of fate determinants by the two daughter cells. In vertebrates, asymmetric fate determinants, such as Par3 and Mib, are only now starting to be identified. Here we show that, during mitosis of neural precursors in zebrafish, directional trafficking of Sara endosomes to one of the daughters can function as such a determinant. In asymmetric lineages, where one daughter cell becomes a neuron (n cell) whereas the other divides again to give rise to two neurons (p cell), we found that the daughter that inherits most of the Sara endosomes acquires the p fate. Sara endosomes carry an endocytosed pool of the Notch ligand DeltaD, which is thereby itself distributed asymmetrically. Sara and Notch are both essential for cell fate assignation within asymmetric lineages. Therefore, the Sara endosome system determines the fate decision between neuronal differentiation and mitosis in asymmetric lineages and thereby contributes to controlling the number of neural precursors and differentiated neurons during neurogenesis in a vertebrate.
Published: 2015

49. Molecular interaction between the chaperone Hsc70 and the N-terminal flank of huntingtin exon 1 modulates aggregation

Author: Luc Bousset, Virginie Redeker, Gemma Ruiz-Arlandis, Elodie Monsellier, Ronald Melki, Institut des Neurosciences Paris-Saclay (NeuroPSI), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)
Subjects: animal structures, Huntingtin, HSC70 Heat-Shock Proteins, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Nerve Tissue Proteins, macromolecular substances, Plasma protein binding, Protein aggregation, MESH: HSC70 Heat-Shock Proteins, Fibril, Biochemistry, Mass Spectrometry, Exon, Humans, MESH: Protein Binding, MESH: Nerve Tissue Proteins, Molecular Biology, Genetics, MESH: Mass Spectrometry, Huntingtin Protein, MESH: Humans, biology, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Peptides, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Molecular Bases of Disease, Exons, Cell Biology, 3. Good health, Cell biology, Chaperone (protein), embryonic structures, biology.protein, MESH: Molecular Chaperones, Peptides, MESH: Exons, Molecular Chaperones, Protein Binding
Abstract: International audience; The aggregation of polyglutamine (polyQ)-containing proteins is at the origin of nine neurodegenerative diseases. Molecular chaperones prevent the aggregation of polyQ-containing proteins. The exact mechanism by which they interact with polyQ-containing, aggregation-prone proteins and interfere with their assembly is unknown. Here we dissect the mechanism of interaction between a huntingtin exon 1 fragment of increasing polyQ lengths (HttEx1Qn), the aggregation of which is tightly associated with Huntington's disease, and molecular chaperone Hsc70. We show that Hsc70, together with its Hsp40 co-chaperones, inhibits HttEx1Qn aggregation and modifies the structural, seeding, and infectious properties of the resulting fibrils in a polyQ-independent manner. We demonstrate that Hsc70 binds the 17-residue-long N-terminal flank of HttEx1Qn, and we map Hsc70-HttEx1Qn surface interfaces at the residue level. Finally, we show that this interaction competes with homotypic interactions between the N termini of different HttEx1Qn molecules that trigger the aggregation process. Our results lay the foundations of future therapeutic strategies targeting huntingtin aggregation in Huntington disease.
Published: 2015

50. Transcriptional alterations and chromatin remodeling in polyglutamine diseases

Author: Dominique Helmlinger, Laszlo Tora, Didier Devys, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Ataxin 7, Transcription, Genetic, MESH: Spinocerebellar Ataxias, [SDV]Life Sciences [q-bio], MESH: DNA Repeat Expansion, Nerve Tissue Proteins, Biology, Models, Biological, Chromatin remodeling, Gene product, Mice, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Transcriptional regulation, Animals, Humans, Spinocerebellar Ataxias, Histone acetyltransferase activity, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Mice, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Ataxin-7, 0303 health sciences, DNA Repeat Expansion, MESH: Humans, MESH: Peptides, MESH: Transcription, Genetic, MESH: Chromatin Assembly and Disassembly, MESH: Models, Biological, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Chromatin Assembly and Disassembly, medicine.disease, Phenotype, MESH: Models, Animal, Models, Animal, Spinocerebellar ataxia, biology.protein, Peptides, 030217 neurology & neurosurgery
Abstract: International audience; Transcriptional dysregulation is now thought to be a common feature of polyglutamine disorders, including the spinocerebellar ataxias (SCAs). However, the precise causes of transcriptional alterations and how they relate to the observed phenotype remain elusive. Transcriptional impairment differs in different diseases, possibly reflecting the specific functions of the disease-causing proteins. The SCA7 gene product, ataxin-7, is a subunit of a transcriptional coactivator complex (called STAGA or TFTC) that has histone acetyltransferase activity. Studies on the effect of mutant ataxin-7 on STAGA function suggest that chromatin remodeling and transcriptional alterations are key pathologic events in SCA type 7. These studies could reveal how polyglutamine expansions alter the transcriptional regulation of genes required for neuronal function.
Published: 2006

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