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Published ahead of print on September 3, 2009
J Am Soc Nephrol 20: 2328-2337, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2008121224
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BASIC RESEARCH

p53 Regulates Metanephric Development

Zubaida Saifudeen, Susana Dipp, Jana Stefkova, Xiao Yao, Sarah Lookabaugh and Samir S. El-Dahr

Section of Pediatric Nephrology, Department of Pediatrics, and the Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana

Correspondence: Dr. Zubaida Saifudeen, Tulane University Health Sciences Center, Department of Pediatrics, SL-37, 1430 Tulane Avenue, New Orleans, LA 70112. Phone: 504-988-5377; Fax: 504-988-1852; E-mail: zubisaif{at}tulane.edu

Received for publication December 1, 2008. Accepted for publication June 18, 2009.

p53 is best known as a tumor suppressor that regulates cell-cycle, differentiation, and apoptosis pathways, but its potential role in embryonic development and organogenesis remains controversial. Here, p53–/– embryos bred on C57Bl6 background exhibited a spectrum of congenital abnormalities of the kidney and urinary tract, including ureteric bud (UB) ectopia, double ureters/collecting systems, delayed primary branching of the UB, and hypoplastic metanephroi. We observed ectopic UB outgrowth from the Wolffian duct (WD) in one third of p53–/– embryos. The prevalence of duplex was higher in embryos than in neonates, and ex vivo organ culture suggested that ectopic ureters can regress over time, leaving behind a dysplastic pole ("segmental dysgenesis"). Transgenic expression of dominant negative p53 or conditional inactivation of p53 in the UB but not in the metanephric mesenchyme lineage recapitulated the duplex phenotype. Mechanistically, p53 inactivation in the WD associated with enhanced sensitivity to glial cell line–derived neurotrophic factor (GDNF)-induced ectopic budding and potentiated phosphatidylinositol-3 kinase activation by GDNF in UB cells. Unlike several other models of UB ectopia, hypersensitivity of p53–/– WD to GDNF is not accompanied by reduced Sprouty-1 or anterior expansion of the GDNF domain. In summary, our data lend support for a restrictive role for p53 activity in UB outgrowth from the WD.


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