P53 enables metabolic fitness and self-renewal of nephron progenitor cells

Yuwen Li, Jiao Liu, Wencheng Li, Aaron Brown, Melody Baddoo, Marilyn Li, Thomas Carroll, Leif Oxburgh, Yumei Feng, Zubaida Saifudeen

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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+;p53fl/fl) induces progressive depletion of Cited1+/Six2+ selfrenewing 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+;p53fl/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+;p53fl/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+;p53fl/fl CM belong to glucose metabolism and adhesion and/ or migration pathways. Mutant cells exhibit a ~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.

Original languageEnglish (US)
Pages (from-to)1228-1241
Number of pages14
JournalDevelopment (Cambridge)
Volume142
Issue number7
DOIs
StatePublished - Apr 1 2015

Keywords

  • Metabolism
  • Nephron
  • P53
  • Progenitors
  • Self-renewal

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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