Abstract
The p53 family members p73 and p63 have been implicated in various aspects of stem cell regulation. Here, we have asked whether they work together to regulate stem cell biology, focusing upon neural precursor cells (NPCs) in the adult murine brain. By studying mice that are haploinsufficient for p63 and/or p73, we show that these two proteins cooperate to ensure appropriate NPC self-renewal and long-term maintenance in the hippocampus and forebrain, and that when both are haploinsufficient, the NPC deficits are significantly greater than haploinsufficiency for either alone. We show that, in the case of p63+/− mice, this decrease in adult NPCs is caused by enhanced apoptosis. However, when p73 is coincidently haploinsufficient, this rescues the enhanced apoptosis of p63+/− NPCs under both basal conditions and following genotoxic stress, instead causing increased cellular senescence. This increase in cellular senescence is likely due, at least in part, to increased levels of basal DNA damage and p53 activation, as genetic ablation of p53 completely rescues the senescence phenotype observed in p63+/−; p73+/− mice. Thus, the presence of p73 determines whether p63+/− NPCs exhibit increased p53-dependent apoptosis or senescence. Together, these studies demonstrate that p63 and p73 cooperate to maintain adult NPC pools through regulation of p53 function; p63 antagonizes p53 to promote cellular survival, whereas p73 regulates self-renewal and p53-mediated apoptosis versus senescence.
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Abbreviations
- NPC:
-
neural precursor cell
- SGZ:
-
subgranular zone
- SVZ:
-
subventricular zone
- PUMA:
-
p53-upregulated modulator of apoptosis
- Sox2:
-
SRY (sex determining region Y)-box 2
- BrdU:
-
5-bromo-2'-deoxyuridine
- NeuN:
-
neuronal nuclei (also known as Feminizing Locus on X-3, or Fox-3)
- CC3:
-
cleaved caspase-3
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick end labeling
- ZVAD-fmk:
-
carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone
- SA-β-Gal:
-
senescence-associated β-galactosidase
- γH2AX:
-
phospho-histone H2A, member X
- RT-PCR:
-
reverse transcriptase PCR
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Acknowledgements
This work was funded by CIHR grants MOP-38021 and MOP-14446 to FDM and DRK. GIC was funded by fellowships from the Heart and Stroke Foundation of Canada and Becas Chile, FDM and DRK hold Canada Research Chairs, and FDM is an HHMI Senior International Research Scholar. We thank Frank McKeon (Harvard) for the generous gift of p73 knockout mice, and Alea Mills (Cold Spring Harbour Laboratories) for the gift of p63 knockout mice. We thank Benigno Aquino and Vania Ariosa for technical assistance.
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Fatt, M., Cancino, G., Miller, F. et al. p63 and p73 coordinate p53 function to determine the balance between survival, cell death, and senescence in adult neural precursor cells. Cell Death Differ 21, 1546–1559 (2014). https://doi.org/10.1038/cdd.2014.61
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DOI: https://doi.org/10.1038/cdd.2014.61
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