p53 regulates metanephric development.
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.
Saifudeen
Zubaida
Z
Section of Pediatric Nephrology, Department of Pediatrics, and the Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. zubisaif@tulane.edu
Dipp
Susana
S
Stefkova
Jana
J
Yao
Xiao
X
Lookabaugh
Sarah
S
El-Dahr
Samir S
SS
D000818:Animals; D015870:Gene Expression; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D007668:Kidney / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology*; D051379:Mice; D038081:Organogenesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D014928:Wolffian Ducts / Q000196:embryology
D051100:Glial Cell Line-Derived Neurotrophic Factor; D016159:Tumor Suppressor Protein p53