p53 Enables metabolic fitness and self-renewal of nephron progenitor cells.
Authors Li Y, Liu J, Li W, Brown A, Baddoo M, Li M, Carroll T, Oxburgh L, Feng Y,
Saifudeen Z
Submitted By Zubaida Saifudeen on 10/29/2015
Status Published
Journal Development (Cambridge, England)
Year 2015
Date Published 4/1/2015
Volume : Pages 142 : 1228 - 41
PubMed Reference 25804735
Abstract Contrary to its classic role in restraining cell proliferation, we demonstrate
here a divergent function of p53 in the maintenance 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 ~ 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
self-renewal of nephron progenitors.

Investigators with authorship
Thomas CarrollUniversity of Texas Southwestern
Leif OxburghMaine Medical Center Research Institute
Zubaida SaifudeenTulane University Health Sciences Center Campus