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 journalArticle

11 Citations (Scopus)

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<sup>+</sup>;p53<sup>fl/fl</sup>) induces progressive depletion of Cited1<sup>+</sup>/Six2<sup>+</sup> 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<sup>+</sup>;p53<sup>fl/fl</sup> cap has 30% fewer Six2(GFP<sup>+</sup>) cells. Apoptotic index is unchanged, whereas proliferation index is significantly reduced in accordance with cell cycle analysis showing disproportionately fewer Six2Cre<sup>+</sup>;p53<sup>fl/fl</sup> cells in the S and G2/M phases compared with Six2Cre<sup>+</sup>;p53<sup>+/+</sup> 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<sup>+</sup>) CM cells revealed that the top downregulated genes in Six2Cre<sup>+</sup>;p53<sup>fl/fl</sup> 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

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Nephrons
Mesoderm
Stem Cells
Kidney
Neural Cell Adhesion Molecules
G2 Phase
Financial Management
Cadherins
Stromal Cells
Cell Adhesion
Cell Division
Energy Metabolism
Reactive Oxygen Species
Cell Cycle
Arterial Pressure
Down-Regulation
Epithelium
Adenosine Triphosphate
Cell Proliferation
RNA

Keywords

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

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

Cite this

Li, Y., Liu, J., Li, W., Brown, A., Baddoo, M., Li, M., ... Saifudeen, Z. (2015). P53 enables metabolic fitness and self-renewal of nephron progenitor cells. Development (Cambridge), 142(7), 1228-1241. https://doi.org/10.1242/dev.111617

P53 enables metabolic fitness and self-renewal of nephron progenitor cells. / Li, Yuwen; Liu, Jiao; Li, Wencheng; Brown, Aaron; Baddoo, Melody; Li, Marilyn; Carroll, Thomas; Oxburgh, Leif; Feng, Yumei; Saifudeen, Zubaida.

In: Development (Cambridge), Vol. 142, No. 7, 01.04.2015, p. 1228-1241.

Research output: Contribution to journalArticle

Li, Y, Liu, J, Li, W, Brown, A, Baddoo, M, Li, M, Carroll, T, Oxburgh, L, Feng, Y & Saifudeen, Z 2015, 'P53 enables metabolic fitness and self-renewal of nephron progenitor cells', Development (Cambridge), vol. 142, no. 7, pp. 1228-1241. https://doi.org/10.1242/dev.111617
Li, Yuwen ; Liu, Jiao ; Li, Wencheng ; Brown, Aaron ; Baddoo, Melody ; Li, Marilyn ; Carroll, Thomas ; Oxburgh, Leif ; Feng, Yumei ; Saifudeen, Zubaida. / P53 enables metabolic fitness and self-renewal of nephron progenitor cells. In: Development (Cambridge). 2015 ; Vol. 142, No. 7. pp. 1228-1241.
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