title: p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity.
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.
authors.affiliation: Neurobiology Research Group, Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. kippin@psych.ucsb.edu
authors.forename: Tod E
authors.initials: TE
authors.lastname: Kippin
authors.forename: David J
authors.initials: DJ
authors.lastname: Martens
authors.forename: Derek
authors.initials: D
authors.lastname: van der Kooy
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001973:Bromodeoxyuridine; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D016548:Prosencephalon / Q000166:cytology*
chemical_list: C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D001973:Bromodeoxyuridine