title: The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis.
abstract: Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, the role of these proteins in normal CNS development is unknown. Here, we used a conditional gene-targeting approach to inactivate Atrx, specifically in the forebrain of mice. Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal "birthdating" confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Moreover, cortical progenitors isolated from Atrx-null mice undergo enhanced apoptosis upon differentiation. Taken together, our results indicate that ATRX is a critical mediator of cell survival during early neuronal differentiation. Thus, increased neuronal loss may contribute to the severe mental retardation observed in human patients.
authors.affiliation: Molecular Medicine Programs, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
authors.forename: Nathalie G
authors.initials: NG
authors.lastname: Bérubé
authors.forename: Marie
authors.initials: M
authors.lastname: Mangelsdorf
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jagla
authors.forename: Jackie
authors.initials: J
authors.lastname: Vanderluit
authors.forename: David
authors.initials: D
authors.lastname: Garrick
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gibbons
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.forename: David J
authors.initials: DJ
authors.lastname: Picketts
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D018390:Gene Targeting; D006624:Hippocampus / Q000196:embryology* / Q000473:pathology; D038901:X-Linked Intellectual Disability / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019579:Neocortex / Q000196:embryology* / Q000473:pathology; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000473:pathology / Q000502:physiology; D000075924:X-linked Nuclear Protein
chemical_list: D002843:Chromatin; D009687:Nuclear Proteins; D004265:DNA Helicases; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein