PMID:11731455

Citation	Brophy, PD, Ostrom, L, Lang, KM and Dressler, GR (2001) Regulation of ureteric bud outgrowth by Pax2-dependent activation of the glial derived neurotrophic factor gene. Development 128:4747-56
Abstract	The outgrowth of the ureteric bud from the posterior nephric duct epithelium and the subsequent invasion of the bud into the metanephric mesenchyme initiate the process of metanephric, or adult kidney, development. The receptor tyrosine kinase RET and glial cell-derived neurotrophic factor (GDNF) form a signaling complex that is essential for ureteric bud growth and branching morphogenesis of the ureteric bud epithelium. We demonstrate that Pax2 expression in the metanephric mesenchyme is independent of induction by the ureteric bud. Pax2 mutants are deficient in ureteric bud outgrowth and do not express GDNF in the uninduced metanephric mesenchyme. Furthermore, Pax2 mutant mesenchyme is unresponsive to induction by wild-type heterologous inducers. In normal embryos, GDNF is sufficient to induce ectopic ureter buds in the posterior nephric duct, a process inhibited by bone morphogenetic protein 4. However, GDNF replacement in organ culture is not sufficient to stimulate ureteric bud outgrowth from Pax2 mutant nephric ducts, indicating additional defects in the nephric duct epithelium of Pax2 mutants. Pax2 can activate expression of GDNF in cell lines derived from embryonic metanephroi. Furthermore, Pax2 protein can bind to upstream regulatory elements within the GDNF promoter region and can transactivate expression of reporter genes. Thus, activation of GDNF by Pax2 coordinates the position and outgrowth of the ureteric bud such that kidney development can begin.
Links	PubMed
Keywords	Animals; Base Sequence; Binding Sites/genetics; DNA/genetics; DNA/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Drosophila Proteins; Gene Expression Regulation, Developmental; Glial Cell Line-Derived Neurotrophic Factor; Glial Cell Line-Derived Neurotrophic Factor Receptors; Kidney/embryology; Mice; Mice, Mutant Strains; Mutagenesis, Site-Directed; Nerve Growth Factors; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; PAX2 Transcription Factor; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases/genetics; Receptor Protein-Tyrosine Kinases/metabolism; Sequence Homology, Nucleic Acid; Signal Transduction; Transcription Factors/genetics; Transcription Factors/metabolism; Ureter/embryology
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