title: Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression.
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.
authors.affiliation: Departamento de Biología Celular, Universidad de Valencia, Valencia, Spain.
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Marqués-Torrejón
authors.forename: Eva
authors.initials: E
authors.lastname: Porlan
authors.forename: Ana
authors.initials: A
authors.lastname: Banito
authors.forename: Esther
authors.initials: E
authors.lastname: Gómez-Ibarlucea
authors.forename: Andrés J
authors.initials: AJ
authors.lastname: Lopez-Contreras
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernández-Capetillo
authors.forename: Anxo
authors.initials: A
authors.lastname: Vidal
authors.forename: Jesús
authors.initials: J
authors.lastname: Gil
authors.forename: Josema
authors.initials: J
authors.lastname: Torres
authors.forename: Isabel
authors.initials: I
authors.lastname: Fariñas
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse