title: Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells.
abstract: Adult neural stem cell proliferation is dynamic and has the potential for massive self-renewal yet undergoes limited cell division in vivo. Here, we report an epigenetic mechanism regulating proliferation and self-renewal. The recruitment of the PI3K-related kinase signaling pathway and histone H2AX phosphorylation following GABA(A) receptor activation limits subventricular zone proliferation. As a result, NSC self-renewal and niche size is dynamic and can be directly modulated in both directions pharmacologically or by genetically targeting H2AX activation. Surprisingly, changes in proliferation have long-lasting consequences on stem cell numbers, niche size, and neuronal output. These results establish a mechanism that continuously limits proliferation and demonstrates its impact on adult neurogenesis. Such homeostatic suppression of NSC proliferation may contribute to the limited self-repair capacity of the damaged brain.
authors: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Ruani N
authors: RN
authors: Fernando
authors: Boris
authors: B
authors: Eleuteri
authors: Shaimaa
authors: S
authors: Abdelhady
authors: Andre
authors: A
authors: Nussenzweig
authors: Michael
authors: M
authors: Andäng
authors: Patrik
authors: P
authors: Ernfors
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D004260:DNA Repair / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric
chemical_list: D006657:Histones; D019869:Phosphatidylinositol 3-Kinases