Abstract
In the adult brain, continual neurogenesis of olfactory neurons is sustained by the existence of neural stem cells (NSCs) in the subependymal niche. Elimination of the cyclin-dependent kinase inhibitor 1A (p21) leads to premature exhaustion of the subependymal NSC pool, suggesting a relationship between cell cycle control and long-term self-renewal, but the molecular mechanisms underlying NSC maintenance by p21 remain unexplored. Here we identify a function of p21 in the direct regulation of the expression of pluripotency factor Sox2, a key regulator of the specification and maintenance of neural progenitors. We observe that p21 directly binds a Sox2 enhancer and negatively regulates Sox2 expression in NSCs. Augmented levels of Sox2 in p21 null cells induce replicative stress and a DNA damage response that leads to cell growth arrest mediated by increased levels of p19(Arf) and p53. Our results show a regulation of NSC expansion driven by a p21/Sox2/p53 axis.
| Original language | English |
|---|---|
| Journal | Cell Stem Cell |
| Volume | 12 |
| Issue number | 1 |
| Pages (from-to) | 88-100 |
| Number of pages | 13 |
| ISSN | 1934-5909 |
| DOIs | |
| Publication status | Published - 3 Jan 2013 |
| Externally published | Yes |
Keywords
- Adult Stem Cells
- Animals
- Cells, Cultured
- Chromatin Immunoprecipitation
- Cyclin-Dependent Kinase Inhibitor p21
- Immunoblotting
- Immunohistochemistry
- Mice
- Mice, Mutant Strains
- Neural Stem Cells
- Protein Binding
- Reverse Transcriptase Polymerase Chain Reaction
- SOXB1 Transcription Factors