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

TY - JOUR

T1 - Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression

AU - Marqués-Torrejón, M Ángeles

AU - Porlan, Eva

AU - Banito, Ana

AU - Gómez-Ibarlucea, Esther

AU - Lopez-Contreras, Andrés J

AU - Fernández-Capetillo, Oscar

AU - Vidal, Anxo

AU - Gil, Jesús

AU - Torres, Josema

AU - Fariñas, Isabel

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

PY - 2013/1/3

Y1 - 2013/1/3

N2 - 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.

AB - 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.

KW - Adult Stem Cells

KW - Animals

KW - Cells, Cultured

KW - Chromatin Immunoprecipitation

KW - Cyclin-Dependent Kinase Inhibitor p21

KW - Immunoblotting

KW - Immunohistochemistry

KW - Mice

KW - Mice, Mutant Strains

KW - Neural Stem Cells

KW - Protein Binding

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - SOXB1 Transcription Factors

U2 - 10.1016/j.stem.2012.12.001

DO - 10.1016/j.stem.2012.12.001

M3 - Journal article

C2 - 23260487

SN - 1934-5909

VL - 12

SP - 88

EP - 100

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 1

ER -