title: Ascl1/Mash1 promotes brain oligodendrogenesis during myelination and remyelination.
abstract: Oligodendrocytes are the myelin-forming cells of the CNS. They differentiate from oligodendrocyte precursor cells (OPCs) that are produced from progenitors throughout life but more actively during the neonatal period and in response to demyelinating insults. An accurate regulation of oligodendrogenesis is required to generate oligodendrocytes during these developmental or repair processes. We hypothesized that this regulation implicates transcription factors, which are expressed by OPCs and/or their progenitors. Ascl1/Mash1 is a proneural transcription factor previously implicated in embryonic oligodendrogenesis and operating in genetic interaction with Olig2, an essential transcriptional regulator in oligodendrocyte development. Herein, we have investigated the contribution of Ascl1 to oligodendrocyte development and remyelination in the postnatal cortex. During the neonatal period, Ascl1 expression was detected in progenitors of the cortical subventricular zone and in cortical OPCs. Different genetic approaches to delete Ascl1 in cortical progenitors or OPCs reduced neonatal oligodendrogenesis, showing that Ascl1 positively regulated both OPC specification from subventricular zone progenitors as well as the balance between OPC differentiation and proliferation. Examination of remyelination processes, both in the mouse model for focal demyelination of the corpus callosum and in multiple sclerosis lesions in humans, indicated that Ascl1 activity was upregulated along with increased oligodendrogenesis observed in remyelinating lesions. Additional genetic evidence indicated that remyelinating oligodendrocytes derived from Ascl1(+) progenitors/OPCs and that Ascl1 was required for proper remyelination. Together, our results show that Ascl1 function modulates multiple steps of OPC development in the postnatal brain and in response to demyelinating insults.
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakatani
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Martin
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Hessameh
authors.initials: H
authors.lastname: Hassani
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Clavairoly
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Cécile L
authors.initials: CL
authors.lastname: Maire
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Arthur
authors.initials: A
authors.lastname: Viadieu
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Kerninon
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Delmasure
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Frah
authors.affiliation: Medical Research Council National Institute for Medical Research, Division of Molecular Neurobiology, London NW71 AA United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Weber
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakafuku
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.|Assistance Publique-Hôpitaux de Paris, GH Pitié-Salpêtrière, 75013 Paris, France, and.
authors.forename: Bernard
authors.initials: B
authors.lastname: Zalc
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.|Assistance Publique-Hôpitaux de Paris, GH Pitié-Salpêtrière, 75013 Paris, France, and.|Department of Neurology, Yale School of Medicine, New Haven, Connecticut 06511.
authors.forename: Jean-Léon
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: Medical Research Council National Institute for Medical Research, Division of Molecular Neurobiology, London NW71 AA United Kingdom.
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.|Assistance Publique-Hôpitaux de Paris, GH Pitié-Salpêtrière, 75013 Paris, France, and.
authors.forename: Brahim
authors.initials: B
authors.lastname: Nait-Oumesmar
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière, e 75013 Paris, France.|Inserm UMR_S 975, 75013 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Parras
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000502:physiology*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C499317:Ascl1 protein, mouse