Abstract
The molecular mechanisms that regulate adult neural precursor cell (NPC) survival, and thus maintain adult neurogenesis, are not well defined. Here, we investigate the role of p63, a p53 family member, in adult NPC function in mice. Conditional ablation of p63 in adult NPCs or p63 haploinsufficiency led to reduced numbers of NPCs and newborn neurons in the neurogenic zones of the hippocampus and lateral ventricles and in the olfactory bulb. These reductions were attributable to enhanced apoptosis of NPCs and newborn neurons and were rescued by inhibition of caspase activity, p53, or the p53 apoptotic effector PUMA (p53-upregulated modulator of apoptosis). Moreover, these cellular deficits were functionally important because they led to perturbations in hippocampus-dependent memory formation. These results indicate that p63 regulates the numbers of adult NPCs and adult-born neurons as well as neural stem cell-dependent cognitive functions, and that it does so, at least in part, by inhibiting p53-dependent cell death.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult Stem Cells / physiology*
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Animals
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Bromodeoxyuridine / metabolism
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Survival / physiology
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Cells, Cultured
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Cerebral Ventricles / cytology
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Conditioning, Psychological / physiology
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Cues
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Exploratory Behavior / drug effects
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Exploratory Behavior / physiology*
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Fear / psychology
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Hippocampus / physiology*
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Intermediate Filament Proteins / genetics
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Maze Learning / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Nerve Tissue Proteins / genetics
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Nestin
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Neural Stem Cells / physiology*
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Neurogenesis / drug effects
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Neurogenesis / genetics
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Neurogenesis / physiology*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Proteins / genetics
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RNA, Untranslated
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Tamoxifen / pharmacology
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcriptional Activation / drug effects
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Tumor Suppressor Protein p53 / genetics
Substances
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Gt(ROSA)26Sor non-coding RNA, mouse
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Intermediate Filament Proteins
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Nerve Tissue Proteins
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Nes protein, mouse
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Nestin
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Phosphoproteins
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Proteins
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RNA, Untranslated
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Trans-Activators
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Trp63 protein, mouse
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Tumor Suppressor Protein p53
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Tamoxifen
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Bromodeoxyuridine