期刊
DEVELOPMENT
卷 142, 期 7, 页码 1228-1241出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.111617
关键词
P53; Self-renewal; Nephron; Metabolism; Progenitors
资金
- National Institutes of Health: Center of Biomedical Research Excellence [NIH-NIGMS P20RR017659]
- PNCE Pilot Grant [NIH-NIDDK P50DK096373]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetic Complications Consortium (DiaComp) [DK076169]
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR017659] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL122770] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U24DK076169, R01DK090127, P30DK079328, R01DK080004, R01DK095057, P50DK096373] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM103518, P30GM103337] Funding Source: NIH RePORTER
Contrary to its classic role in restraining cell proliferation, we demonstrate here a divergent function of p53 in themaintenance of self-renewal of the nephron progenitor pool in the embryonic mouse kidney. Nephron endowment is regulated by progenitor availability and differentiation potential. Conditional deletion of p53 in nephron progenitor cells (Six2Cre(+); p53(fl/fl)) induces progressive depletion of Cited1(+)/Six2(+) self-renewing progenitors and loss of cap mesenchyme (CM) integrity. The Six2(p53-null) CM is disorganized, with interspersed stromal cells and an absence of a distinct CM-epithelia and CM-stroma interface. Impaired cell adhesion and epithelialization are indicated by decreased E-cadherin and NCAM expression and by ineffective differentiation in response to Wnt induction. The Six2Cre(+);p53(fl/fl) cap has 30% fewer Six2(GFP(+)) cells. Apoptotic index is unchanged, whereas proliferation index is significantly reduced in accordance with cell cycle analysis showing disproportionately fewer Six2Cre(+);p53(fl/fl) cells in the S and G2/M phases compared with Six2Cre(+);p53(+/+) cells. Mutant kidneys are hypoplastic with fewer generations of nascent nephrons. A significant increase in mean arterial pressure is observed in early adulthood in both germline and conditional Six2(p53-null) mice, linking p53-mediated defects in kidney development to hypertension. RNA-Seq analyses of FACS-isolated wild-type and Six2(GFP(+)) CM cells revealed that the top downregulated genes in Six2Cre(+);p53(fl/fl) CM belong to glucose metabolism and adhesion and/or migration pathways. Mutant cells exhibit a similar to 50% decrease in ATP levels and a 30% decrease in levels of reactive oxygen species, indicating energy metabolism dysfunction. In summary, our data indicate a novel role for p53 in enabling the metabolic fitness and selfrenewal of nephron progenitors.
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