Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 14, Pages 5837-5842Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1014993108
Keywords
DNA damage response; subventricular zone astrocytes; self-repair
Categories
Funding
- Swedish Research Council
- Swedish Cancer Foundation
- Swedish Child Cancer Foundation
- Swedish Brain Foundation
- Bertil Hallsten Research Foundation
- EU
- KI Strategic Neuroscience Programme
- Wallenberg Scholar Award
- ERC [232675]
- Knut and Alice Wallenberg Foundation (Center for Live Imaging of Cells at Karolinska Institutet)
- Federation of the Societies of Biochemistry and Molecular Biology
- Swedish Childhood Cancer Foundation
- European Research Council (ERC) [232675] Funding Source: European Research Council (ERC)
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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.
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