title: Regenerative capacity of neural precursors in the adult mammalian brain is under the control of p53.
abstract: The question of whether or not stem cell loss drives aging in the brain has not been fully resolved. Here, we used mice over-expressing the short isoform of p53 (DeltaNp53 or p44) as a model of aging to gain insight into the cellular mechanisms underlying age-related functional deficits in the brain. By BrdU labeling, we observed an accelerated decline in the number of subventricular zone proliferating cells with age in p44Tg mice compared to mice with normal p53 expression. A 2-3-fold reduction in the number of slowly dividing stem cells was evident in the subventricular zone of 9-12-month-old p44Tg mice, but not in younger p44Tg mice or in normal mice. Consequently, the supply of new olfactory bulb neurons was also reduced. The number and size of neurospheres generated from subventricular zone cells from p44Tg mice was significantly reduced, and cells derived from these neurospheres had limited self-renewal and amplification capacities. At the cellular level, p44 lengthened the cell cycle and affected cell cycle reentry properties, evident by an increased proportion of cells in G0. At the functional level, p44 expression resulted in impaired olfactory discrimination in 15-16-month-old mice. This phenotype is driven by constitutive activation of p53 and constitutive expression of p21(Cip1/waf1) in neural stem cells. Our results demonstrate that p53 plays a crucial role in the maintenance of the regenerative capacity of the brain by regulating the proliferation of stem and progenitor cells.
authors.affiliation: Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908-1392, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Medrano
authors.forename: Melissa
authors.initials: M
authors.lastname: Burns-Cusato
authors.forename: Marybless B
authors.initials: MB
authors.lastname: Atienza
authors.forename: Donya
authors.initials: D
authors.lastname: Rahimi
authors.forename: Heidi
authors.initials: H
authors.lastname: Scrable
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D012038:Regeneration / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology
chemical_list: D016159:Tumor Suppressor Protein p53