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

Marqués-Torrejón, María Ángeles; Porlan, Eva; Banito, Ana; Gómez-Ibarlucea, Esther; López-Contreras, Andrés J.; Fernández-Capetillo, Óscar; Vidal, Anxo; Gil, Jesús; Torres, Josema; Fariñas, Isabel

doi:10.1016/j.stem.2012.12.001

Cited by 173 publications

(153 citation statements)

References 55 publications

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“…An analogous mechanism has been described for proper regionalization of the optic cup during eye development [33]. On the other hand, p21 has been recently shown as a major player in the control of expansion of NSCs through negative regulation of the Sox2 gene [34]. Consistent with these findings, our results show p21 expression in fate-restricted progenitors, suggesting a possible link with Sox2 downregulation and granule lineage specification.…”

Section: Discussionsupporting

confidence: 91%

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

et al. 2013

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Neural stem cells are highly susceptible to radiogenic DNA damage, however, little is known about their mechanisms of DNA damage response (DDR) and the long-term consequences of genotoxic exposure. Patched1 heterozygous mice (Ptc1 1/2 ) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1 1/2 mice dramatically increases the frequency and shortens the latency of MB. In this model, we investigated the mechanisms through which multipotent neural progenitors (NSCs) and faterestricted progenitor cells (PCs) of the cerebellum respond to DNA damage induced by radiation, and the long-term developmental and oncogenic consequences. These responses were assessed in mice exposed to low (0.25 Gy) or high (3 Gy) radiation doses at embryonic day 13.5 (E13.5), when NSCs giving rise to the cerebellum are specified but the external granule layer (EGL) has not yet formed, or at E16.5, during the expansion of granule PCs to form the EGL. We found crucial differences in DDR and apoptosis between NSCs and fate-restricted PCs, including lack of p21 expression in NSCs. NSCs also appear to be resistant to oncogenesis from low-dose radiation exposure but more vulnerable at higher doses. In addition, the pathway to DNA repair and the pattern of oncogenic alterations were strongly dependent on age at exposure, highlighting a differentiation-stage specificity of DNA repair pathways in NSCs and PCs. These findings shed light on the mechanisms used by NSCs and PCs to maintain genome integrity during neurogenesis and may have important implications for radiation risk assessment and for development of targeted therapies against brain tumors.

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Section: Discussionsupporting

confidence: 91%

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

et al. 2013

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“…Our data suggest that when cultured cells are crowded, transcriptional up-regulation of this CDKi (p15) is driven by direct synergistic derepression of its promoter via loss of p21 and Runx1. Previously, p21 and Runx1 were shown capable of acting as transcriptional repressors (14,33,35,36), and we find that they bind to the predicted DNA sites on the p15 promoter. Additionally, p15 expression is able to hamper cell cycle progression of cultured keratinocytes.…”

Section: Discussionsupporting

confidence: 50%

Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo

Lee

Hoi

Lilja

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mechanisms of tissue stem cell (SC) quiescence control are important for normal homeostasis and for preventing cancer. Cyclin-dependent kinase inhibitors (CDKis) are known inhibitors of cell cycle progression. We document CDKis expression in vivo during hair follicle stem cell (HFSC) homeostasis and find p21 (cyclin-dependent kinase inhibitor 1a, Cdkn1a), p57, and p15 up-regulated at quiescence onset. p21 appears important for HFSC timely onset of quiescence. Conversely, we find that Runx1 (runt related transcription factor 1), which is known for promoting HFSC proliferation, represses p21, p27, p57, and p15 transcription in HFSC in vivo. Intriguingly, in cell culture, tumors, and normal homeostasis, Runx1 and p21 interplay modulates proliferation in opposing directions under the different conditions. Unexpectedly, Runx1 and p21 synergistically limit the extent of HFSC quiescence in vivo, which antagonizes the role of p21 as a cell cycle inhibitor. Importantly, we find in cultured keratinocytes that Runx1 and p21 bind to the p15 promoter and synergistically repress p15 mRNA transcription, thereby restraining cell cycle arrest. This documents a surprising ability of a CDKi (p21) to act as a direct transcriptional repressor of another CDKi (p15). We unveil a robust in vivo mechanism that enforces quiescence of HFSCs, and a context-dependent role of a CDKi (p21) to limit quiescence of SCs, potentially by directly down-regulating mRNA levels of (an)other CDKi(s).AML1 | skin | malignancy | pulse-chase | H2B-GFP

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“…Examples include genes or members of pathways that have previously been described as targets of the pRb-E2f family in the brain, such as Sox2 8,35 and members of the Notch/Hes (Notch1, Hes5, Jag1, Rbpj and Numb) 11,14 and Fgf pathways (Fgfr2 and Fgfr3). 17 Additional genes include components of the Wnt (Wnt6, Fzd5, Dll4, Gsk3b, Apc and Tcf3) and Tgf-β signaling pathways (Tgfbr1, Bmp7, Smad4&7 and Acvr2b), the transcription factors Ascl1, Pax6 and Lhx2, the chromatin regulators Dnmt1, Mbd1 and members of the Polycomb/Trithorax families (Ezh2, Eed, Epc1 and Mll1).…”

Section: Resultsmentioning

confidence: 99%

Tissue-specific targeting of cell fate regulatory genes by E2f factors

et al. 2015

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Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. Identification of the genes targeted by E2 promoter binding factor (E2f) transcription factors, effectors of the pRb/E2f cell cycle pathway, will provide essential insights into these mechanisms. We identified the promoter regions bound by three neurogenic E2f factors in neural precursor cells in a genome-wide manner. Through bioinformatic analyses and integration of published genomic data sets we uncovered hundreds of transcriptionally active E2f-bound promoters corresponding to genes that control cell fate processes, including key transcriptional regulators and members of the Notch, fibroblast growth factor, Wnt and Tgf-β signaling pathways. We also demonstrate a striking enrichment of the CCCTC binding factor transcription factor (Ctcf) at E2f3-bound nervous system-related genes, suggesting a potential regulatory co-factor for E2f3 in controlling differentiation. Finally, we provide the first demonstration of extensive tissue specificity among E2f target genes in mammalian cells, whereby E2f3 promoter binding is well conserved between neural and muscle precursors at genes associated with cell cycle processes, but is tissue-specific at differentiation-associated genes. Our findings implicate the cell cycle pathway as a widespread regulator of cell fate genes, and suggest that E2f3 proteins control cell typespecific differentiation programs by regulating unique sets of target genes. This work significantly enhances our understanding of how the cell cycle machinery impacts cell fate and differentiation, and will importantly drive further discovery regarding the mechanisms of cell fate control and transcriptional regulation in the brain, as well as in other tissues.

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

Cited by 173 publications

References 55 publications

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo

Tissue-specific targeting of cell fate regulatory genes by E2f factors

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