p53 Regulates Metanephric Development
| Autor: | Samir S. El-Dahr, Susana Dipp, Zubaida Saifudeen, Xiao Yao, Jana Stefkova, Sarah Lookabaugh |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Tumor suppressor gene Organogenesis Mesenchyme Gene Expression Kidney Mesonephric duct Mice Neurotrophic factors Internal medicine medicine Glial cell line-derived neurotrophic factor Animals Glial Cell Line-Derived Neurotrophic Factor Budding biology Embryogenesis Wolffian Ducts General Medicine Cell biology Basic Research medicine.anatomical_structure Endocrinology Nephrology Ureteric bud biology.protein Tumor Suppressor Protein p53 |
| Zdroj: | Journal of the American Society of Nephrology. 20:2328-2337 |
| ISSN: | 1046-6673 |
| DOI: | 10.1681/asn.2008121224 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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