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1. Corrigendum to 'O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis' [JHEP Reports 6 [2024] 100878]

Author

Paula Ortega-Prieto, Lucia Parlati, Fadila Benhamed, Marion Regnier, Isadora Cavalcante, Mélanie Montabord, Rachel Onifarasoaniaina, Maryline Favier, Natasa Pavlovic, Julie Magusto, Michèle Cauzac, Patrick Pagesy, Jérémie Gautheron, Chantal Desdouets, Sandra Guilmeau, Tarik Issad, and Catherine Postic

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Published
2024
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2. O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis

Author

Paula Ortega-Prieto, Lucia Parlati, Fadila Benhamed, Marion Regnier, Isadora Cavalcante, Mélanie Montabord, Rachel Onifarasoaniaina, Maryline Favier, Natasa Pavlovic, Julie Magusto, Michèle Cauzac, Patrick Pagesy, Jérémie Gautheron, Chantal Desdouets, Sandra Guilmeau, Tarik Issad, and Catherine Postic

Subjects
OGT, Oxidative stress, Liver fibrosis, Carbohydrate intake, Ketogenic diet, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: O-GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In the liver, O-GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. Methods: To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGTLKO) were generated and challenged with different carbohydrate- and lipid-containing diets. Results: Analyses of 4-week-old OGTLKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress-induced apoptosis was also elevated in OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver. Conclusions: These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGTLKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis. Impact and Implications: Our study shows that hepatocyte-specific deletion of O-GlcNAc transferase (OGT) leads to severe liver injury, reinforcing the importance of O-GlcNAcylation and OGT for hepatocyte homeostasis and survival. Our study also validates the Ogt liver-deficient mouse as a valuable model for the study of advanced liver fibrosis. Importantly, as the severe hepatic fibrosis of Ogt liver-deficient mice could be fully prevented upon feeding on a ketogenic diet (i.e. very-low-carbohydrate, high-fat diet) this work underlines the potential interest of nutritional intervention as antifibrogenic strategies.

Published
2024
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3. Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

Author

Alice Gilbert, Xabier Elorza-Vidal, Armelle Rancillac, Audrey Chagnot, Mervé Yetim, Vincent Hingot, Thomas Deffieux, Anne-Cécile Boulay, Rodrigo Alvear-Perez, Salvatore Cisternino, Sabrina Martin, Sonia Taïb, Aontoinette Gelot, Virginie Mignon, Maryline Favier, Isabelle Brunet, Xavier Declèves, Mickael Tanter, Raul Estevez, Denis Vivien, Bruno Saubaméa, and Martine Cohen-Salmon

Subjects
MLC, MLC1, gliovascular unit, astrocytes, development, Medicine, Science, Biology (General), QH301-705.5
Abstract

Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare type of leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation that lead to ataxia, spasticity, and cognitive decline. During postnatal development (from P5 to P15 in the mouse), MLC1 forms a membrane complex with GlialCAM (another astrocytic transmembrane protein) at the junctions between perivascular astrocytic processes. Perivascular astrocytic processes along with blood vessels form the gliovascular unit. It was not previously known how MLC1 influences the physiology of the gliovascular unit. Here, using the Mlc1 knock-out mouse model of MLC, we demonstrated that MLC1 controls the postnatal development and organization of perivascular astrocytic processes, vascular smooth muscle cell contractility, neurovascular coupling, and intraparenchymal interstitial fluid clearance. Our data suggest that MLC is a developmental disorder of the gliovascular unit, and perivascular astrocytic processes and vascular smooth muscle cell maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.

Published
2021
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4. The role of the glucose-sensing transcription factor carbohydrate-responsive element-binding protein pathway in termite queen fertility

Author

David Sillam-Dussès, Robert Hanus, Michael Poulsen, Virginie Roy, Maryline Favier, and Mireille Vasseur-Cognet

Subjects
reproduction, phenotypic plasticity, carbohydrate-responsive element-binding protein, transcription factor, social insects, lipogenesis, Biology (General), QH301-705.5
Abstract

Termites are among the few animals that themselves can digest the most abundant organic polymer, cellulose, into glucose. In mice and Drosophila, glucose can activate genes via the transcription factor carbohydrate-responsive element-binding protein (ChREBP) to induce glucose utilization and de novo lipogenesis. Here, we identify a termite orthologue of ChREBP and its downstream lipogenic targets, including acetyl-CoA carboxylase and fatty acid synthase. We show that all of these genes, including ChREBP, are upregulated in mature queens compared with kings, sterile workers and soldiers in eight different termite species. ChREBP is expressed in several tissues, including ovaries and fat bodies, and increases in expression in totipotent workers during their differentiation into neotenic mature queens. We further show that ChREBP is regulated by a carbohydrate diet in termite queens. Suppression of the lipogenic pathway by a pharmacological agent in queens elicits the same behavioural alterations in sterile workers as observed in queenless colonies, supporting that the ChREBP pathway partakes in the biosynthesis of semiochemicals that convey the signal of the presence of a fertile queen. Our results highlight ChREBP as a likely key factor for the regulation and signalling of queen fertility.

Published
2016
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6. Activation of Wnt/beta-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells.

Author

Mounira Abiola, Maryline Favier, Eleni Christodoulou-Vafeiadou, Anne-Lise Pichard, Isabelle Martelly, and Isabelle Guillet-Deniau

Subjects
Medicine, Science
Abstract

Intramyocellular lipid accumulation is strongly related to insulin resistance in humans, and we have shown that high glucose concentration induced de novo lipogenesis and insulin resistance in murin muscle cells. Alterations in Wnt signaling impact the balance between myogenic and adipogenic programs in myoblasts, partly due to the decrease of Wnt10b protein. As recent studies point towards a role for Wnt signaling in the pathogenesis of type 2 diabetes, we hypothesized that activation of Wnt signaling could play a crucial role in muscle insulin sensitivity.Here we demonstrate that SREBP-1c and Wnt10b display inverse expression patterns during muscle ontogenesis and regeneration, as well as during satellite cells differentiation. The Wnt/beta-catenin pathway was reactivated in contracting myotubes using siRNA mediated SREBP-1 knockdown, Wnt10b over-expression or inhibition of GSK-3beta, whereas Wnt signaling was inhibited in myoblasts through silencing of Wnt10b. SREBP-1 knockdown was sufficient to induce Wnt10b protein expression in contracting myotubes and to activate the Wnt/beta-catenin pathway. Conversely, silencing Wnt10b in myoblasts induced SREBP-1c protein expression, suggesting a reciprocal regulation. Stimulation of the Wnt/beta-catenin pathway i) drastically decreased SREBP-1c protein and intramyocellular lipid deposition in myotubes; ii) increased basal glucose transport in both insulin-sensitive and insulin-resistant myotubes through a differential activation of Akt and AMPK pathways; iii) restored insulin sensitivity in insulin-resistant myotubes.We conclude that activation of Wnt/beta-catenin signaling in skeletal muscle cells improved insulin sensitivity by i) decreasing intramyocellular lipid deposition through downregulation of SREBP-1c; ii) increasing insulin effects through a differential activation of the Akt/PKB and AMPK pathways; iii) inhibiting the MAPK pathway. A crosstalk between these pathways and Wnt/beta-catenin signaling in skeletal muscle opens the exciting possibility that organ-selective modulation of Wnt signaling might become an attractive therapeutic target in regenerative medicine and to treat obese and diabetic populations.

Published
2009
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7. In mice and humans, brain microvascular contractility matures postnatally

Author

Leila Slaoui, Alice Gilbert, Armelle Rancillac, Barbara Delaunay-Piednoir, Audrey Chagnot, Quentin Gerard, Gaëlle Letort, Philippe Mailly, Noémie Robil, Antoinette Gelot, Mathilde Lefebvre, Maryline Favier, Karine Dias, Laurent Jourdren, Laetitia Federici, Sylvain Auvity, Salvatore Cisternino, Denis Vivien, Martine Cohen-Salmon, Anne-Cécile Boulay, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), GIP Cyceron (Cyceron), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GenoSplice [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional d'Orléans (CHRO), Plateforme Histologie, Immunomarquage et Microdissection laser [Institut Cochin] (HistIM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Cohen-Salmon, Martine, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), GenomiqueENS (Genomique ENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Université Paris Descartes - Paris 5 (UPD5)

Subjects
[SDV] Life Sciences [q-bio], Postnatal development, Histology, General Neuroscience, [SDV]Life Sciences [q-bio], Vascular smooth muscle cell, microvessel contractility, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Anatomy, Cerebral blood flow, Brain microvessels Postnatal development Vascular smooth muscle cell microvessel contractility Cerebral blood flow, Brain microvessels
Abstract

International audience; Although great efforts to characterize the embryonic phase of brain microvascular system development have been made, its postnatal maturation has barely been described. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific orpreferentially expressed transcripts. We found that endothelial cells (EC), vascular smooth muscle cells (VSMC) and fibroblasts (FB) follow specific molecular maturation programs over this time period. Focusing on VSMCs, we showed that arteriolar VSMC network expands and becomes contractile resulting in a greater cerebral blood flow (CBF), with heterogenous developmental trajectories within cortical regions. Samples of human brain cortex showed the same postnatal maturation process. Thus, the postnatal phase is a critical period during which arteriolar VSMC contractility required for vessel tone and brain perfusion is acquired and mature.

Published
2022
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8. In mice and humans, brain microvascular contractility matures postnatally Brain microvessel post-natal maturation

Author

Leila Slaoui, Alice Gilbert, Armelle Rancillac, Audrey Chagnot, Laetitia Federici, Quentin Gerard, Antoinette Gelot, Mathilde Becmeur-Lefebvre, Maryline Favier, Noémie Robil, Gaëlle Letort, Karine Dias, Laurent Jourdren, Philippe Mailly, Sylvain Auvity, Salvatore Cisternino, Denis Vivien, Martine Cohen-Salmon, and Anne-Cécile Boulay

Abstract

Although great efforts to characterize the embryonic phase of brain microvascular system development have been made, its postnatal maturation has barely been described. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific or -preferentially expressed transcripts. We found that endothelial cells (EC), vascular smooth muscle cells (VSMC) and fibroblasts (FB) follow specific molecular maturation programs over this time period. Focusing on VSMCs, we showed that arteriolar VSMC network expands and becomes contractile resulting in a greater cerebral blood flow (CBF). Samples of human brain cortex showed the same postnatal maturation process. Thus, the postnatal phase is a critical period during which arteriolar VSMC contractility required for vessel tone and brain perfusion is acquired and mature.

Published
2022
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9. In mice and humans, the brain’s blood vessels mature postnatally to acquire barrier and contractile properties

Author

Gilbert A, Robil N, Salvatore Cisternino, Antoinette Gelot, Philippe Mailly, Auvity S, Gaëlle Letort, Slaoui L, Laurent Jourdren, Dias K, Anne-Cécile Boulay, Armelle Rancillac, Maryline Favier, Federici L, Martine Cohen-Salmon, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), GenoSplice [Paris], Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), and Cohen-Salmon, Martine

Subjects
Vascular smooth muscle, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mural cell, Contractility, 03 medical and health sciences, 0302 clinical medicine, Smooth Muscle Actin, Endothelial cell, Myosin, medicine, MYH11, Actin, 030304 developmental biology, Blood-brain barrier, 0303 health sciences, Chemistry, P- glycoprotein, Embryogenesis, Myosin heavy chain 11, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, ABCB1, Human brain, Cell biology, Postnatal development, medicine.anatomical_structure, Vascular smooth muscle cell, cardiovascular system, 030217 neurology & neurosurgery
Abstract

The brain dense vascular network is essential for distributing oxygen and nutrients to neural cells. The network develops during embryogenesis and leads to the formation of the endothelial blood-brain barrier (BBB). This barrier is surrounded by mural cells (pericytes and vascular smooth muscle cells (VSMCs)) and fibroblasts. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific or -preferentially expressed transcripts. We found that endothelial cells (ECs), VSMCs and fibroblasts follow specific molecular maturation programs over this time period. In particular, ECs acquire P-glycoprotein (P-gP)-mediated efflux capacities. The arterial VSMC network expands, acquires contractile proteins (such as smooth muscle actin (SMA) and myosin heavy chain 11 (Myh11)) and becomes contractile. We also analyzed samples of human brain cortex from the early prenatal stage through to adulthood: the expression of endothelial P-gP increased at birth and Myh11 in VSMCs acts as a developmental switch (as in the mouse) at birth and up to the age of 2 of 5 years. Thus, in both mice and humans, the early postnatal phase is a critical period during which the essential properties of cerebral blood vessels (i.e. the endothelial efflux of xenobiotics and other molecules, and the VSMC contractility required for vessel tone and brain perfusion) are acquired and mature.

Published
2021

10. Author response: Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

Author

Sonia Taïb, Mickael Tanter, Mervé Yetim, Denis Vivien, Xavier Declèves, Alice Gilbert, Vincent Hingot, Bruno Saubaméa, Martine Cohen-Salmon, Armelle Rancillac, Salvatore Cisternino, Audrey Chagnot, Xabier Elorza-Vidal, Raúl Estévez, Isabelle Brunet, Rodrigo Alvear-Perez, Aontoinette Gelot, Maryline Favier, Virginie Mignon, Sabrina Martin, Thomas Deffieux, and Anne-Cécile Boulay

Subjects
Developmental disorder, Pathology, medicine.medical_specialty, Megalencephalic leukoencephalopathy with subcortical cysts, business.industry, medicine, medicine.disease, business
Published
2021
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11. Deletion of the

Author

Marie-Sophie Girault, Cécile Viollet, Ahmed Ziyyat, Laurence Stouvenel, Rémi Pierre, Maryline Favier, Côme Ialy-Radio, Sophie Dupuis, and Sandrine Barbaux

Subjects
Male, mouse model, Congenic, Locus (genetics), Fertilization in Vitro, Biology, Quantitative trait locus, sperm, Article, Catalysis, Inorganic Chemistry, lcsh:Chemistry, Mice, Pregnancy, Testis, Spata3, Animals, Physical and Theoretical Chemistry, Acrosome, Spermatogenesis, Molecular Biology, Gene, lcsh:QH301-705.5, Spectroscopy, Infertility, Male, Mice, Knockout, Organic Chemistry, Chromosome, Proteins, General Medicine, Lipid Droplets, Sperm, Phenotype, Computer Science Applications, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, lcsh:Biology (General), lcsh:QD1-999, Sperm Motility, Female, CRISPR-Cas Systems, infertility, Gene Deletion
Abstract

Thanks to the analysis of an Interspecific Recombinant Congenic Strain (IRCS), we previously defined the Mafq1 quantitative trait locus as an interval on mouse Chromosome 1 associated with male hypofertility and ultrastructural abnormalities. We identified the Spermatogenesis associated protein 3 gene (Spata3 or Tsarg1) as a pertinent candidate within the Mafq1 locus and performed the CRISPR-Cas9 mediated complete deletion of the gene to investigate its function. Male mice deleted for Spata3 were normally fertile in vivo but exhibited a drastic reduction of efficiency in in vitro fertilization assays. Mobility parameters were normal but ultrastructural analyses revealed acrosome defects and an overabundance of lipids droplets in cytoplasmic remnants. The deletion of the Spata3 gene reproduces therefore partially the phenotype of the hypofertile IRCS strain.

Published
2021

12. Mutations in TTC29, Encoding an Evolutionarily Conserved Axonemal Protein, Result in Asthenozoospermia and Male Infertility

Author

Marhaba Chaudhry, Sergey N. Savinov, Caroline Cazin, Gérard Gacon, Laurence Stouvenel, Abbas Daneshipour, Christophe Arnoult, Jean-Philippe Wolf, François Guillonneau, Raoudha Zouari, Pierre F. Ray, Maëlle Givelet, Jean-Fabrice Nsota Mbango, Alain Schmitt, Emmanuel Dulioust, Amir Amiri-Yekta, Lazhar Halouani, Denis Dacheux, Zeinab Sakheli, Patrick Lorès, Selima Fourati Ben Mustapha, Côme Ialy-Radio, Charles Coutton, Seyedeh Hanieh Hosseini, Aminata Touré, Lucile Ferreux, Maryline Favier, Mélanie Bonhivers, Zine-Eddine Kherraf, Catherine Patrat, Derrick R. Robinson, Ahmed Ziyyat, Ouafi Marrakchi, Elma El Khouri, Marjorie Whitfield, Marcio Do Cruzeiro, 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), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), 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), AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Service d'Histologie-Embryologie, Biologie de la Reproduction (CECOS Paris Cochin), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Clinique de Promotion des Sciences de la Reproduction - Les Jasmins (CPSR), Clinique de Promotion des Sciences de la Reproduction, Clinique de la reproduction les Jasmins, Polyclinique les Jasmins [Tunis], Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Génétique et Biologie du Développement, Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), University of Massachusetts [Amherst] (UMass Amherst), University of Massachusetts System (UMASS), Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre 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 [2016-2019] (UGA [2016-2019]), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Microbiologie Fondamentale et Pathogénicité (MFP), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-12-BSV1-0011,MUCOFERTIL,La protéine TAT1 (SLC26A8), partenaire et activateur de CFTR dans le spermatozoïde, au carrefour des infertilités masculines et de la mucoviscidose.(2012), and ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011)

Subjects
Male, 0301 basic medicine, Axoneme, Trypanosoma brucei brucei, TPR, Fertilization in Vitro, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Flagellum, Biology, Asthenozoospermia, sperm, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, Article, Frameshift mutation, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, trypanosome, Trypanosomiasis, Intraflagellar transport, TTC29, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Genetics, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Gene, Infertility, Male, Genetics (clinical), mouse, asthenozoospermia, 030219 obstetrics & reproductive medicine, Sperm flagellum, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Sperm, Mice, Inbred C57BL, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Tetratricopeptide, 030104 developmental biology, Mutation, MMAF, Female, flagella, infertility, Microtubule-Associated Proteins
Abstract

International audience; In humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, which accounts for the main sperm defect encountered in infertile men. Herein we focused on morphological abnormalities of the sperm flagellum (MMAF), a phenotype also termed "short tails," which constitutes one of the most severe sperm morphological defects resulting in asthenozoospermia. In previous work based on whole-exome sequencing of a cohort of 167 MMAF-affected individuals, we identified bi-allelic loss-of-function mutations in more than 30% of the tested subjects. In this study, we further analyzed this cohort and identified five individuals with homozygous truncating variants in TTC29, a gene preferentially and highly expressed in the testis, and encoding a tetratricopeptide repeat-containing protein related to the intraflagellar transport (IFT). One individual carried a frameshift variant, another one carried a homozygous stop-gain variant, and three carried the same splicing variant affecting a consensus donor site. The deleterious effect of this last variant was confirmed on the corresponding transcript and protein product. In addition, we produced and analyzed TTC29 loss-of-function models in the flagellated protist T. brucei and in M. musculus. Both models confirmed the importance of TTC29 for flagellar beating. We showed that in T. brucei the TPR structural motifs, highly conserved between the studied orthologs, are critical for TTC29 axonemal localization and flagellar beating. Overall our work demonstrates that TTC29 is a conserved axonemal protein required for flagellar structure and beating and that TTC29 mutations are a cause of male sterility due to MMAF.

Published
2019
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13. Extracorporeal Shock Waves Therapy Delivered by Aries Improves Erectile Dysfunction in Spontaneously Hypertensive Rats Through Penile Tissue Remodeling and Neovascularization

Author

Rana, Assaly, François, Giuliano, Pierre, Clement, Miguel, Laurin, Maryline, Favier, Pearline, Teo, Jacques, Bernabe, Laurent, Alexandre, and Delphine, Behr-Roussel

Subjects
Low-Intensity Extracorporeal Shock Wave Therapy, Erectile Dysfunction, Hypertension, Fibrosis
Abstract

Background Low-intensity extracorporeal shock wave therapy (Li-ESWT) has been reported to improve erectile function in patients with moderate-to-severe erectile dysfunction (ED) or even convert phosphodiesterase type 5 inhibitors nonresponders to responders. ED is highly prevalent in hypertensive patients. The effect of Li-ESWT on an animal model of hypertension-associated ED has not been reported. Aim To investigate the effect of Li-ESWT on hypertension-associated ED and provide plausible mechanisms of action of Li-ESWT on local mechanisms of penile erection. Methods Spontaneously hypertensive rats (SHRs) in the active group (n = 13) received Li-ESWT at energy flux density 0.06 mJ/mm2 (Aries; Dornier MedTech, Wessling, Germany) twice weekly for 6 weeks. The emitter was set to zero for SHRs in the sham group (n = 12). Erectile function was assessed 4 weeks post-treatment by monitoring intracavernosal pressure (ICP) in response to electrical stimulation of cavernous nerve before and after single dose of 0.3 mg/kg intravenous sildenafil. Cavernosal tissue was then evaluated for collagen/smooth muscle content, neuronal nitric oxide synthase (nNOS), and vascular endothelial factor (CD31) expression. Outcomes Erectile function was assessed with ICP, erectile tissue remodeling was studied by smooth muscle/collagen ratio, nNOS and CD31 were semiquantitatively evaluated on cavernosal sections. Results The improvement of ICP parameters was greater in Li-ESWT–treated rats compared with controls with and without sildenafil. Sildenafil led to 20% increase in area under the intracavernosal pressure curve measured during the entire response/mean arterial pressure at 10 Hz in ESWT_SHR + sildenafil compared with ESWT_SHR. The smooth muscle/collagen ratio increased 2.5-fold in Li-ESWT compared with sham. Expression of CD31 tended to be increased whereas nNOS was unchanged. Conclusions Li-ESWT by Aries may represent an effective noninvasive therapeutic alternative and a relevant add-on therapy to phosphodiesterase type 5 inhibitors for ED in hypertensive patients, and it is suggested that it acts via remodeling of the penile tissue and promoting cavernosal vascularization. Assaly R, Giuliano F, Clement P, et al. Extracorporeal Shock Waves Therapy Delivered by Aries Improves Erectile Dysfunction in Spontaneously Hypertensive Rats Through Penile Tissue Remodeling and Neovascularization. Sex Med 2019;7:441–450

Published
2019

14. Emerging Role of IL-4-Induced Gene 1 as a Prognostic Biomarker Affecting the Local T-Cell Response in Human Cutaneous Melanoma

Author

Jan Philipp Ramspott, Flavia Castellano, Lounes Djerroudi, Valérie Molinier-Frenkel, Yolande Richard, Maryline Favier, Armelle Prévost-Blondel, Anne Vincent Salomon, Benoit Terris, Marie-Françoise Avril, Lloyd Bod, Kurt S. Zaenker, Fériel Bekkat, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et de cytologie pathologiques [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie et Oncogenese des Tumeurs Lymphoides, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Equipe 09, Service d'immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de dermatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)

Subjects
0301 basic medicine, Adult, Cytotoxicity, Immunologic, Male, Skin Neoplasms, Regulatory T cell, Sentinel lymph node, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, CD8-Positive T-Lymphocytes, L-Amino Acid Oxidase, Biochemistry, T-Lymphocytes, Regulatory, 03 medical and health sciences, Immune system, medicine, Biomarkers, Tumor, Tumor Microenvironment, Cytotoxic T cell, Humans, Molecular Biology, Melanoma, ComputingMilieux_MISCELLANEOUS, Aged, Immune Evasion, Neoplasm Staging, Aged, 80 and over, Immunity, Cellular, business.industry, Macrophages, FOXP3, Forkhead Transcription Factors, Cell Biology, Middle Aged, medicine.disease, Prognosis, Survival Analysis, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Cutaneous melanoma, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, CD8
Abstract

Several studies have emphasized the importance of immune composition of the melanoma microenvironment for clinical outcome. The contribution of IL4I1, a phenylalanine oxidase with immunoregulatory functions, has not been yet explored. Here we studied a primary cutaneous melanoma series from stage I–III patients to investigate the association between in situ IL4I1 expression and clinical parameters or tumor-infiltrating T-cell subsets. IL4I1 was detected in 87% of tumors and was mainly expressed by tumor-associated macrophages and very rare FoxP3+ regulatory T cells. The proportion of IL4I1+ cells was higher in patients with an ulcerated melanoma or with a positive sentinel lymph node and tended to correlate with a rapid relapse and shorter overall survival. This proportion also correlated positively with the presence of regulatory T cells and negatively with the presence of cytotoxic CD8+ T cells. The location of IL4I1+ cells may also be relevant to predict prognosis, because their presence near tumor cells was associated with sentinel lymph node invasion and higher melanoma stage. Collectively, our data show that IL4I1+ cells shape the T-cell compartment and are associated with a higher risk of poor outcome in melanoma, supporting a key role for IL4I1 in immune evasion.

Published
2018
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15. Correction: Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils

Author

Pascale Tacnet-Delorme, Delphine Ohayon, Céline Candalh, Etienne Weiss, Coralie Pintard, Véronique Witko-Sarsat, Pham My-Chan Dang, Maryline Favier, Jean-Claude Marie, Alessia De Chiara, Nathalie Thieblemont, Simon Chatfield, Jamel El-Benna, Julie Mocek, Margarita Hurtado-Nedelec, Gilles Renault, Viviana Marzaioli, Philippe Frachet, Isabelle Lagoutte, Dominique Housset, Francine Walker, Dominique Desplancq, Charaf Benarafa, and Sabrina Sofia Burgener

Subjects
Cytosol, NADPH oxidase, biology, Chemistry, Immunology, biology.protein, Immunology and Allergy, Ncf1 gene, Proliferating cell nuclear antigen, Cell biology
Published
2019
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16. The role of the glucose-sensing transcription factor carbohydrate-responsive element-binding protein pathway in termite queen fertility

Author

Maryline Favier, Robert Hanus, Virginie Roy, Michael Poulsen, David Sillam-Dussès, Mireille Vasseur-Cognet, Institut d'écologie et des sciences de l'environnement de Paris (iEES), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA), Laboratoire d'Ethologie Expérimentale et Comparée (LEEC), Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB / CAS), Czech Academy of Sciences [Prague] (CAS), Department for Food Chemistry, National Food Institute, Danish Technical University, Centre for Social Evolution (CSE), Department of Biology [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Department of Plant and Environmental Sciences [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by a maturation grant from the Institute of Research for Development (IRD) received by D.S.D. and M.V.C. (RVO: 61388963), Czech Science Foundation (14-12774S) to R.H. and a Villum Kann Rasmussen Foundation Young Investigator Fellowship (VKR10101) to M.P., Institut d'écologie et des sciences de l'environnement de Paris ( IEES ), Institut National de la Recherche Agronomique ( INRA ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Ethologie Expérimentale et Comparée ( LEEC ), Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ), Institute of Organic Chemistry and Biochemistry [Praha], Czech Academy of Sciences [Prague] ( ASCR ), Centre for Social Evolution, Section for Ecology and Evolution, Department of Biology, University of Copenhagen ( KU ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC), Department of Plant and Environmental Sciences [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Department of Biology [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bos, Mireille, Institut d'écologie et des sciences de l'environnement de Paris (IEES), Czech Academy of Sciences [Prague] (ASCR), and Vasseur-Cognet, Mireille

Subjects
0301 basic medicine, Immunology, education, Isoptera, Biology, phenotypic plasticity, General Biochemistry, Genetics and Molecular Biology, reproduction, 03 medical and health sciences, Downregulation and upregulation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Tissue Distribution, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Interaction Maps, Carbohydrate-responsive element-binding protein, lcsh:QH301-705.5, Gene, Transcription factor, carbohydrate-responsive element-binding protein, transcription factor, social insects, lipogenesis, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Research Articles, Phylogeny, General Neuroscience, Research, Correction, Pyruvate carboxylase, Up-Regulation, Fatty acid synthase, 030104 developmental biology, Fertility, Glucose, lcsh:Biology (General), ChREBP Pathway, Biochemistry, Lipogenesis, biology.protein, Insect Proteins, Female, Signal Transduction, Transcription Factors
Abstract

Termites are among the few animals that themselves can digest the most abundant organic polymer, cellulose, into glucose. In mice and Drosophila , glucose can activate genes via the transcription factor carbohydrate-responsive element-binding protein (ChREBP) to induce glucose utilization and de novo lipogenesis. Here, we identify a termite orthologue of ChREBP and its downstream lipogenic targets, including acetyl-CoA carboxylase and fatty acid synthase. We show that all of these genes, including ChREBP, are upregulated in mature queens compared with kings, sterile workers and soldiers in eight different termite species. ChREBP is expressed in several tissues, including ovaries and fat bodies, and increases in expression in totipotent workers during their differentiation into neotenic mature queens. We further show that ChREBP is regulated by a carbohydrate diet in termite queens. Suppression of the lipogenic pathway by a pharmacological agent in queens elicits the same behavioural alterations in sterile workers as observed in queenless colonies, supporting that the ChREBP pathway partakes in the biosynthesis of semiochemicals that convey the signal of the presence of a fertile queen. Our results highlight ChREBP as a likely key factor for the regulation and signalling of queen fertility.

Published
2016
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17. The antiangiogenic insulin receptor substrate-1 antisense oligonucleotide aganirsen impairs AU-rich mRNA stability by reducing 14-3-3β-tristetraprolin protein complex, reducing inflammation and psoriatic lesion size in patients

Author

Amine Kadi, Corrine Lesaffre, Salman Al-Mahmood, Neijib Doss, Bernadette Darne, Antoine Ferry, Maryline Favier, Jean-Pascal Conduzorgues, and Sylvie Colin

Subjects
Male, medicine.medical_specialty, Administration, Topical, RNA Stability, Oligonucleotides, Inflammation, Angiogenesis Inhibitors, Pilot Projects, Lesion, chemistry.chemical_compound, Downregulation and upregulation, Double-Blind Method, Tristetraprolin, Internal medicine, Psoriasis, medicine, Humans, RNA, Messenger, Skin, Pharmacology, AU Rich Elements, biology, Dose-Response Relationship, Drug, Middle Aged, medicine.disease, IRS1, Vascular endothelial growth factor, Insulin receptor, Endocrinology, Treatment Outcome, chemistry, Immunology, Microvessels, biology.protein, Insulin Receptor Substrate Proteins, Molecular Medicine, Cytokines, Tumor necrosis factor alpha, Female, medicine.symptom
Abstract

Increased inflammation and aberrant angiogenesis underlie psoriasis. Here, we report that the inhibition of insulin receptor substrate-1 (IRS-1) expression with aganirsen resulted in a dose-dependent reduction (P < 0.0001) in IRS-1 protein in the cytoplasm, while IRS-1 protein remained quantitatively unchanged in the perinuclear environment. Aganirsen induced a dose-dependent increase in serine-phosphorylated IRS-1 in the soluble perinuclear-nuclear fraction, inducing IRS-1-14-3-3β protein association (P < 0.001), thereby impairing 14-3-3β-tristetraprolin protein complex and AU-rich mRNA's stability (P < 0.001). Accordingly, aganirsen inhibited (P < 0.001) in vitro the expression of interleukin-8 (IL-8), IL-12, IL-22, and tumor necrosis factor alpha (TNFα), four inflammatory mediators containing mRNA with AU-rich regions. To demonstrate the clinical relevance of this pathway, we tested the efficacy of aganirsen by topical application in a pilot, double-blind, randomized, dose-ranging study in 12 psoriatic human patients. After 6 weeks of treatment, least square mean differences with placebo were -38.9% (95% confidence interval, -75.8 to -2.0%) and -37.4% (-74.3 to -0.5%) at the doses of 0.86 and 1.72 mg/g, respectively. Lesion size reduction was associated with reduced expression of IRS-1 (P < 0.01), TNFα (P < 0.0001), and vascular endothelial growth factor (P < 0.01); reduced keratinocyte proliferation (P < 0.01); and the restoration (P < 0.02) of normal levels of infiltrating CD4(+) and CD3(+) lymphocytes in psoriatic skin lesions. These results suggest that aganirsen is a first-in-class of a new generation of antiangiogenic medicines combining anti-inflammatory activities. Aganirsen-induced downregulation of inflammatory mediators characterized by AU-rich mRNA likely underlies its beneficial clinical outcome in psoriasis. These results justify further large-scale clinical studies to establish the dose of aganirsen and its long-term efficacy in psoriasis.

Published
2014

18. Six1 and Six4 gene expression is necessary to activate the fast-type muscle gene program in the mouse primary myotome

Author

Pascal Maire, Julien Giordani, Nicolas Sgarioto, Josiane Demignon, Maryline Favier, Yubing Liu, Stéphane D. Vincent, Alexandre Blais, Claire Niro, Isabelle Guillet-Deniau, VINCENT, Stéphane, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bases Génétiques, Moléculaires et Cellulaires du Développement (BGMCD), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ottawa Institute of Systems Biology, University of Ottawa [Ottawa], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], C.N. was supported successively by a fellowship from the 'Ministère de la recherche et de l'enseignement supérieur' and from the 'Association Française contre les Myopathies' (AFM). Financial support was provided by the Institut National pour la Santé et la Recherche Médicale (INSERM), the AFM, the AFM/INSERM «Cellules souches» programs, the Centre National de la Recherche Scientifique (CNRS), the Agence Nationale pour la Recherche (ANR no. RO5099KK), and the FP6 MYORES European network of excellence. A.B. acknowledges financial support from the Muscular Dystrophy Association. The contribution of the Région Ile de France to the Institut Cochin animal care facility is also acknowledged., Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, and Institut Pasteur [Paris]

Subjects
Muscle Proteins, Fast-type, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Biology, Muscle Development, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, 03 medical and health sciences, Muscle fiber diversity, 0302 clinical medicine, Myotome, Gene expression, medicine, Animals, Myocyte, Transcription factor, Molecular Biology, 030304 developmental biology, Homeodomain Proteins, Regulation of gene expression, 0303 health sciences, Myogenesis, Gene Expression Regulation, Developmental, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Embryo, Mammalian, Molecular biology, Six network, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Somites, Regulatory sequence, Muscle Fibers, Fast-Twitch, Six transcriptional complexes, Trans-Activators, Chromatin immunoprecipitation, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; While the signaling pathways and transcription factors active in adult slow- and fast-type muscles begin to be characterized, genesis of muscle fiber-type diversity during mammalian development remains unexplained. We provide evidence showing that Six homeoproteins are required to activate the fast-type muscle program in the mouse primary myotome. Affymetrix transcriptomal analysis of Six1(-/-)Six4(-/-) E10.5 somites revealed the specific down-regulation of many genes of the fast-type muscle program. This data was confirmed by in situ hybridization performed on Six1(-/-)Six4(-/-) embryos. The first mouse myocytes express both fast-type and slow-type muscle genes. In these fibers, Six1 and Six4 expression is required to specifically activate fast-type muscle genes. Chromatin immunoprecipitation experiments confirm the binding of Six1 and Six4 on the regulatory regions of these muscle genes, and transfection experiments show the ability of these homeoproteins to activate specifically identified fast-type muscle genes. This in vivo wide transcriptomal analysis of the function of the master myogenic determinants, Six, identifies them as novel markers for the differential activation of a specific muscle program during mammalian somitic myogenesis.

Published
2010
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19. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease

Author

Beth L. Thurberg, Alban Vignaud, Emmanuel Richard, Shoichi Takikita, Peter J. Roach, Isabelle Guillet-Deniau, Gaëlle Douillard-Guilloux, Arnaud Ferry, Nina Raben, Catherine Caillaud, and Maryline Favier

Subjects
Male, medicine.medical_specialty, Carbohydrate metabolism, Biology, chemistry.chemical_compound, Mice, Internal medicine, Glycogen storage disease type II, Genetics, medicine, Animals, Humans, Substrate reduction therapy, Glycogen synthase, Muscle, Skeletal, Molecular Biology, Genetics (clinical), Mice, Knockout, Glycogen, Glycogen Storage Disease Type II, Skeletal muscle, alpha-Glucosidases, General Medicine, Enzyme replacement therapy, Articles, medicine.disease, Muscle atrophy, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, Glucose, Glycogen Synthase, chemistry, biology.protein, Female, medicine.symptom, Lysosomes
Abstract

Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Affected individuals store glycogen mainly in cardiac and skeletal muscle tissues resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe infantile form. Enzyme replacement therapy has already proved some efficacy, but results remain variable especially in skeletal muscle. Substrate reduction therapy was successfully used to improve the phenotype in several lysosomal storage disorders. We have recently demonstrated that shRNA-mediated reduction of glycogen synthesis led to a significant reduction of glycogen accumulation in skeletal muscle of GSDII mice. In this paper, we analyzed the effect of a complete genetic elimination of glycogen synthesis in the same GSDII model. GAA and glycogen synthase 1 (GYS1) KO mice were inter-crossed to generate a new double-KO model. GAA/GYS1-KO mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in double-KO mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in GAA/GYS1-KO mice, resulting in improved exercise capacity. These data demonstrate that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in GSDII mice and offers a new perspective for the treatment of Pompe disease.

Published
2009

20. Activation of Wnt/beta-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells

Author

Eleni Christodoulou-Vafeiadou, Isabelle Martelly, Isabelle Guillet-Deniau, Anne-Lise Pichard, Maryline Favier, and Mounira Abiola

Subjects
Indoles, medicine.medical_treatment, Muscle Fibers, Skeletal, lcsh:Medicine, Cell Biology/Cell Signaling, Physiology/Muscle and Connective Tissue, Myoblasts, Diabetes and Endocrinology/Obesity, Glycogen Synthase Kinase 3, Mice, Oximes, Insulin, lcsh:Science, Cells, Cultured, beta Catenin, Multidisciplinary, Glucose Transporter Type 4, biology, Wnt signaling pathway, LRP6, LRP5, medicine.anatomical_structure, Sterol Regulatory Element Binding Protein 1, Muscle Contraction, Signal Transduction, Research Article, medicine.medical_specialty, Beta-catenin, Satellite Cells, Skeletal Muscle, MAP Kinase Signaling System, Down-Regulation, Deoxyglucose, Insulin resistance, Internal medicine, medicine, Animals, Gene Silencing, RNA, Messenger, Glycogen Synthase Kinase 3 beta, lcsh:R, Adenylate Kinase, Skeletal muscle, Biological Transport, medicine.disease, Lipid Metabolism, Rats, Wnt Proteins, Insulin receptor, Endocrinology, Glucose, biology.protein, Physiology/Cell Signaling, lcsh:Q, Proto-Oncogene Proteins c-akt
Abstract

Background Intramyocellular lipid accumulation is strongly related to insulin resistance in humans, and we have shown that high glucose concentration induced de novo lipogenesis and insulin resistance in murin muscle cells. Alterations in Wnt signaling impact the balance between myogenic and adipogenic programs in myoblasts, partly due to the decrease of Wnt10b protein. As recent studies point towards a role for Wnt signaling in the pathogenesis of type 2 diabetes, we hypothesized that activation of Wnt signaling could play a crucial role in muscle insulin sensitivity. Methodology/Principal Findings Here we demonstrate that SREBP-1c and Wnt10b display inverse expression patterns during muscle ontogenesis and regeneration, as well as during satellite cells differentiation. The Wnt/β-catenin pathway was reactivated in contracting myotubes using siRNA mediated SREBP-1 knockdown, Wnt10b over-expression or inhibition of GSK-3β, whereas Wnt signaling was inhibited in myoblasts through silencing of Wnt10b. SREBP-1 knockdown was sufficient to induce Wnt10b protein expression in contracting myotubes and to activate the Wnt/β-catenin pathway. Conversely, silencing Wnt10b in myoblasts induced SREBP-1c protein expression, suggesting a reciprocal regulation. Stimulation of the Wnt/β-catenin pathway i) drastically decreased SREBP-1c protein and intramyocellular lipid deposition in myotubes; ii) increased basal glucose transport in both insulin-sensitive and insulin-resistant myotubes through a differential activation of Akt and AMPK pathways; iii) restored insulin sensitivity in insulin-resistant myotubes. Conclusions/Significance We conclude that activation of Wnt/β-catenin signaling in skeletal muscle cells improved insulin sensitivity by i) decreasing intramyocellular lipid deposition through downregulation of SREBP-1c; ii) increasing insulin effects through a differential activation of the Akt/PKB and AMPK pathways; iii) inhibiting the MAPK pathway. A crosstalk between these pathways and Wnt/β-catenin signaling in skeletal muscle opens the exciting possibility that organ-selective modulation of Wnt signaling might become an attractive therapeutic target in regenerative medicine and to treat obese and diabetic populations.

Published
2009

21. Genesis of muscle fiber-type diversity during mouse embryogenesis relies on Six1 and Six4 gene expression

Author

Anthony Guernec, Josiane Demignon, Ruijin Huang, Isabelle Guillet-Deniau, Laure Strochlic, Anne-Françoise Richard, Claire Legay, Nicolas Sgarioto, Fabien Le Grand, Julien Pujol, Pascal Maire, Maryline Favier, Nicolas Cagnard, Iori Sakakibara, and Alain Schmitt

Subjects
Six/Sine oculis, Time Factors, Muscle Fibers, Skeletal, Synaptogenesis, Embryonic Development, Nerve Tissue Proteins, Fast-type, Biology, Muscle Development, Transcriptome, Mice, Muscle fiber diversity, Microscopy, Electron, Transmission, Myofibrils, Myotome, Gene expression, medicine, Myocyte, Animals, Drosophila Proteins, Molecular Biology, Ca2+homeostasis, Cells, Cultured, In Situ Hybridization, Oligonucleotide Array Sequence Analysis, Homeodomain Proteins, Mice, Knockout, Network of genes, Skeletal muscle, Gene Expression Regulation, Developmental, Cell Biology, Blotting, Northern, Embryo, Mammalian, HDAC4, Phenotype, Molecular biology, Immunohistochemistry, medicine.anatomical_structure, Muscle Fibers, Slow-Twitch, Muscle Fibers, Fast-Twitch, Developmental Biology, Transcription Factors
Abstract

Adult skeletal muscles in vertebrates are composed of different types of myofibers endowed with distinct metabolic and contraction speed properties. Genesis of this fiber-type heterogeneity during development remains poorly known, at least in mammals. Six1 and Six4 homeoproteins of the Six / sine oculis family are expressed throughout muscle development in mice, and Six1 protein is enriched in the nuclei of adult fast-twitch myofibers. Furthermore, Six1/Six4 proteins are known to control the early activation of fast-type muscle genes in myocytes present in the mouse somitic myotome. Using double Six1 : Six4 mutants ( SixdKO ) to dissect in vivo the genesis of muscle fiber-type heterogeneity, we analyzed here the phenotype of the dorsal/epaxial muscles remaining in SixdKO . We show by electron microscopy analysis that the absence of these homeoproteins precludes normal sarcomeric organization of the myofiber leading to a dystrophic aspect, and by immunohistochemistry experiments a deficiency in synaptogenesis. Affymetrix transcriptome analysis of the muscles remaining in E18.5 SixdKO identifies a major role for these homeoproteins in the control of genes that are specifically activated in the adult fast/glycolytic myofibers, particularly those controlling Ca 2+ homeostasis. Absence of Six1 and Six4 leads to the development of dorsal myofibers lacking expression of fast-type muscle genes, and mainly expressing a slow-type muscle program. The absence of restriction of the slow-type program during the fetal period in SixdKO back muscles is associated with a decreased HDAC4 protein level, and subcellular relocalization of the transcription repressor Sox6. Six genes thus behave as essential global regulators of muscle gene expression, as well as a central switch to drive the skeletal muscle fast phenotype during fetal development.

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22. Srf-Dependent Paracrine Signals Produced by Myofibers Control Satellite Cell-Mediated Skeletal Muscle Hypertrophy

Author

Nicolas Cagnard, Luis Garcia, Athanassia Sotiropoulos, Guillaume Précigout, Maryline Favier, Dany Graindorge, David Tuil, Laura Collard, Sabrina Batonnet-Pichon, Charlotte Lahoute, Sophie Hébrard, Dominique Daegelen, and Aline Guerci

Subjects
medicine.medical_specialty, Serum Response Factor, Satellite Cells, Skeletal Muscle, Physiology, Genetic Vectors, Muscle Fibers, Skeletal, Paracrine Communication, Biology, Muscle hypertrophy, Paracrine signalling, Mice, Internal medicine, Serum response factor, medicine, Animals, Muscle, Skeletal, Molecular Biology, Cells, Cultured, Cell Proliferation, Cell fusion, Cell growth, Interleukin-6, Translation (biology), Cell Biology, Hypertrophy, biology.organism_classification, Cell biology, Endocrinology, Cyclooxygenase 2, Satellite (biology), Female, Interleukin-4
Abstract

SummaryAdult skeletal muscles adapt their fiber size to workload. We show that serum response factor (Srf) is required for satellite cell-mediated hypertrophic muscle growth. Deletion of Srf from myofibers and not satellite cells blunts overload-induced hypertrophy, and impairs satellite cell proliferation and recruitment to pre-existing fibers. We reveal a gene network in which Srf within myofibers modulates interleukin-6 and cyclooxygenase-2/interleukin-4 expressions and therefore exerts a paracrine control of satellite cell functions. In Srf-deleted muscles, in vivo overexpression of interleukin-6 is sufficient to restore satellite cell proliferation but not satellite cell fusion and overall growth. In contrast cyclooxygenase-2/interleukin-4 overexpression rescue satellite cell recruitment and muscle growth without affecting satellite cell proliferation, identifying altered fusion as the limiting cellular event. These findings unravel a role for Srf in the translation of mechanical cues applied to myofibers into paracrine signals, which in turn will modulate satellite cell functions and support muscle growth.

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