title: CHD7 maintains neural stem cell quiescence and prevents premature stem cell depletion in the adult hippocampus.
abstract: Neural stem/progenitor cells (NSCs) in the hippocampus produce new neurons throughout adult life. NSCs are maintained in a state of reversible quiescence and the failure to maintain the quiescent state can result in the premature depletion of the stem cell pool. The epigenetic mechanisms that maintain this quiescent state have not been identified. Using an inducible knockout mouse model, we show that the chromatin remodeling factor chromodomain-helicase-DNA-binding protein 7 (CHD7) is essential for maintaining NSC quiescence. CHD7 inactivation in adult NSCs results in a loss of stem cell quiescence in the hippocampus, a transient increase in cell divisions, followed by a significant decline in neurogenesis. This loss of NSC quiescence is associated with the premature loss of NSCs in middle-aged mice. We find that CHD7 represses the transcription of several positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs. These findings directly link CHD7 to pathways involved in NSC quiescence and identify the first chromatin-remodeling factor with a role in NSC quiescence and maintenance. As CHD7 haplo-insufficiency is associated with a range of cognitive disabilities in CHARGE syndrome, our observations may have implications for understanding the basis of these deficits.
authors.affiliation: King's College London, Department of Craniofacial Development and Stem Cell Biology, Guy's Hospital Tower Wing, London, UK.
authors.forename: Kieran M
authors.initials: KM
authors.lastname: Jones
authors.forename: Nemanja
authors.initials: N
authors.lastname: Sarić
authors.forename: John P
authors.initials: JP
authors.lastname: Russell
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Andoniadou
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: M Albert
authors.initials: MA
authors.lastname: Basson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D004265:DNA Helicases / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology
chemical_list: C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; D004265:DNA Helicases; C491434:CHD7 protein, human
keywords: Adult neurogenesis; CHD7; Chromatin remodeling; Hippocampus; Maintenance; Mouse; Neural stem cell; Quiescence; Subgranular zone