title: p53 Enables metabolic fitness and self-renewal of nephron progenitor cells.
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.
authors: Section of Pediatric Nephrology, Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors: Yuwen
authors: Y
authors: Li
authors: Section of Pediatric Nephrology, Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA The Hypertension and Renal Centers of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors: Jiao
authors: J
authors: Liu
authors: Department of Biomedical Science, Colorado State University, Fort Collins, CO 80523, USA.
authors: Wencheng
authors: W
authors: Li
authors: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
authors: Aaron
authors: A
authors: Brown
authors: Tulane Cancer Center.
authors: Melody
authors: M
authors: Baddoo
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Marilyn
authors: M
authors: Li
authors: Department of Internal Medicine (Nephrology) and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Thomas
authors: T
authors: Carroll
authors: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
authors: Leif
authors: L
authors: Oxburgh
authors: Department of Biomedical Science, Colorado State University, Fort Collins, CO 80523, USA.
authors: Yumei
authors: Y
authors: Feng
authors: Section of Pediatric Nephrology, Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA The Hypertension and Renal Centers of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA zubisaif@tulane.edu.
authors: Zubaida
authors: Z
authors: Saifudeen
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001794:Blood Pressure; D002448:Cell Adhesion / Q000235:genetics; D002453:Cell Cycle; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D023281:Genomics; D005854:Germ Cells / Q000166:cytology; D018398:Homeodomain Proteins / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009399:Nephrons / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C102208:Cited1 protein, mouse; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C497420:Six2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C045073:Cre recombinase; D019426:Integrases
keywords: Metabolism; Nephron; P53; Progenitors; Self-renewal