Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression

Cell Stem Cell. 2013 Jan 3;12(1):88-100. doi: 10.1016/j.stem.2012.12.001. Epub 2012 Dec 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / cytology*
  • Adult Stem Cells / metabolism*
  • Animals
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Immunoblotting
  • Immunohistochemistry
  • Mice
  • Mice, Mutant Strains
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism*
  • Protein Binding
  • Reverse Transcriptase Polymerase Chain Reaction
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism*


  • Cyclin-Dependent Kinase Inhibitor p21
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse