P21 Loss Compromises the Relative Quiescence of Forebrain Stem Cell Proliferation Leading to Exhaustion of Their Proliferation Capacity

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2005 Mar 17

PMID 15769947

Citations 203

Authors

Tod E Kippin

David J Martens

Derek van der Kooy

Affiliations

Soon will be listed here.

Abstract

Adult stem cells in various tissues are relatively quiescent. The cell cycle inhibitor p21cip1/waf1 (p21) has been shown to be important for maintaining hematopoietic stem cell quiescence and self-renewal. We examined the role of p21 in the regulation of adult mammalian forebrain neural stem cells (NSCs). We found that p21-/- mice between post-natal age 60-240 d have more NSCs than wild-type (+/+) controls due to higher proliferation rates of p21-/- NSCs. Thereafter, NSCs in p21-/- mice decline and are reduced in number at 16 mo relative to p21+/+ mice. Similarly, both p21-/- and p21+/+ NSCs display self-renewal in vitro; however, p21-/- NSCs display limited in vitro self-renewal (surviving a few passages, then exhausting). Thus, p21 contributes to adult NSC relative quiescence, which we propose is necessary for the life-long maintenance of NSC self-renewal because NSCs may be limited to a finite number of divisions.

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References

Gage F . Mammalian neural stem cells. Science. 2000; 287(5457):1433-8. DOI: 10.1126/science.287.5457.1433. View

Molofsky A, Pardal R, Iwashita T, Park I, Clarke M, Morrison S . Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature. 2003; 425(6961):962-7. PMC: 2614897. DOI: 10.1038/nature02060. View

Weissman I . Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science. 2000; 287(5457):1442-6. DOI: 10.1126/science.287.5457.1442. View

Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M . Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000; 287(5459):1804-8. DOI: 10.1126/science.287.5459.1804. View

Vidal A, Koff A . Cell-cycle inhibitors: three families united by a common cause. Gene. 2000; 247(1-2):1-15. DOI: 10.1016/s0378-1119(00)00092-5. View

Bringold F, Serrano M . Tumor suppressors and oncogenes in cellular senescence. Exp Gerontol. 2000; 35(3):317-29. DOI: 10.1016/s0531-5565(00)00083-8. View

Hayflick L . The illusion of cell immortality. Br J Cancer. 2000; 83(7):841-6. PMC: 2374692. DOI: 10.1054/bjoc.2000.1296. View

Giardino L, Bettelli C, Calza L . In vivo regulation of precursor cells in the subventricular zone of adult rat brain by thyroid hormone and retinoids. Neurosci Lett. 2000; 295(1-2):17-20. DOI: 10.1016/s0304-3940(00)01580-9. View

Tang D, Tokumoto Y, Apperly J, Lloyd A, Raff M . Lack of replicative senescence in cultured rat oligodendrocyte precursor cells. Science. 2001; 291(5505):868-71. DOI: 10.1126/science.1056780. View

10.

Mathon N, Malcolm D, Harrisingh M, Cheng L, Lloyd A . Lack of replicative senescence in normal rodent glia. Science. 2001; 291(5505):872-5. DOI: 10.1126/science.1056782. View

11.

Allsopp R, Cheshier S, Weissman I . Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J Exp Med. 2001; 193(8):917-24. PMC: 2193408. DOI: 10.1084/jem.193.8.917. View

12.

Maslov A, Barone T, Plunkett R, Pruitt S . Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci. 2004; 24(7):1726-33. PMC: 6730468. DOI: 10.1523/JNEUROSCI.4608-03.2004. View

13.

Morshead C, van der Kooy D . Disguising adult neural stem cells. Curr Opin Neurobiol. 2004; 14(1):125-31. DOI: 10.1016/j.conb.2004.01.008. View

14.

Kippin T, Cain S, Masum Z, Ralph M . Neural stem cells show bidirectional experience-dependent plasticity in the perinatal mammalian brain. J Neurosci. 2004; 24(11):2832-6. PMC: 6729516. DOI: 10.1523/JNEUROSCI.0110-04.2004. View

15.

Qiu J, Takagi Y, Harada J, Rodrigues N, Moskowitz M, Scadden D . Regenerative response in ischemic brain restricted by p21cip1/waf1. J Exp Med. 2004; 199(7):937-45. PMC: 2211886. DOI: 10.1084/jem.20031385. View

16.

Ferron S, Mira H, Franco S, Cano-Jaimez M, Bellmunt E, Ramirez C . Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development. 2004; 131(16):4059-70. DOI: 10.1242/dev.01215. View

17.

Enwere E, Shingo T, Gregg C, Fujikawa H, Ohta S, Weiss S . Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci. 2004; 24(38):8354-65. PMC: 6729689. DOI: 10.1523/JNEUROSCI.2751-04.2004. View

18.

Harley C, Futcher A, Greider C . Telomeres shorten during ageing of human fibroblasts. Nature. 1990; 345(6274):458-60. DOI: 10.1038/345458a0. View

19.

Morshead C, van der Kooy D . Postmitotic death is the fate of constitutively proliferating cells in the subependymal layer of the adult mouse brain. J Neurosci. 1992; 12(1):249-56. PMC: 6575699. View

20.

Ogawa M . Differentiation and proliferation of hematopoietic stem cells. Blood. 1993; 81(11):2844-53. View