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Regenerative capacity of neural precursors in the adult mammalian brain is under the control of p53.
Neurobiology of Aging, Issue: 3, Volume: 30, Pages: 483-497. | 2009-03-01
0 Patent citations    33 Scholarly citations     Reference Count: 68
Silvia Medrano;Melissa Burns-Cusato;Marybless B Atienza;Donya Rahimi;Heidi Scrable

摘要

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 (ΔNp53 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 p21Cip1/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.


机构

University of Virginia;Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908-1392, USA.University of VirginiaUniversity of VirginiaUniversity of VirginiaUniversity of Virginia


实验动物:

mouse(小鼠)   

科学仪器:

动物麻醉机   

细胞器官:

progenitor cell    brain    neuron   

基因:

p53 gene   

实验试剂:

Tumor Suppressor Protein p53(D016159)   

免疫治疗:

Biology    Anatomy    Cell biology    Internal medicine    Endocrinology    Adult stem cell    Neural stem cell    Neurosphere    Subventricular zone   

实验方案:

ADME/Tox方案   

文献类型:

journal article;research support, n.i.h., extramural;comparative study;

出版商:

Elsevier Inc.

发表时间:

2009-03-01

基金信息

NIA NIH HHS(R01 AG020915)United States