Cyclin-Dependent Kinase Inhibitor p21 Controls Adult Neural Stem Cell Expansion by Regulating Sox2 Gene Expression

SummaryIn 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 p19Arf and p53. Our results show a regulation of NSC expansion driven by a p21/Sox2/p53 axis.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (288 K)Download as PowerPoint slideHighlights► Adult NSCs require a functional p21 to prevent genomic instability ► p21 negatively controls Sox2 transcription in adult subependymal NSCs ► Overexpression of Sox2 in adult neural stem cells causes replicative stress ► Replicative stress and DNA damage in p21 null NSCs is caused by Sox2 derepression