Regenerative capacity of neural precursors in the adult mammalian brain is under the control of p53

Silvia Medrano, Melissa Burns-Cusato, Marybless B. Atienza, Donya Rahimi, Heidi Scrable

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Pages (from-to)483-497
Number of pages15
JournalNeurobiology of Aging
Volume30
Issue number3
DOIs
StatePublished - Mar 2009
Externally publishedYes

Fingerprint

Brain
Lateral Ventricles
Stem Cells
Cell Cycle
Neural Stem Cells
Olfactory Bulb
Bromodeoxyuridine
Protein Isoforms
Maintenance
Phenotype
Neurons

Keywords

  • ΔNp53
  • Aging
  • Neural stem cells
  • Neurospheres
  • Olfaction
  • Olfactory bulb
  • p44
  • Subventricular zone

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Regenerative capacity of neural precursors in the adult mammalian brain is under the control of p53. / Medrano, Silvia; Burns-Cusato, Melissa; Atienza, Marybless B.; Rahimi, Donya; Scrable, Heidi.

In: Neurobiology of Aging, Vol. 30, No. 3, 03.2009, p. 483-497.

Research output: Contribution to journalArticle

Medrano, Silvia ; Burns-Cusato, Melissa ; Atienza, Marybless B. ; Rahimi, Donya ; Scrable, Heidi. / Regenerative capacity of neural precursors in the adult mammalian brain is under the control of p53. In: Neurobiology of Aging. 2009 ; Vol. 30, No. 3. pp. 483-497.
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