Urogenital development begins when an outgrowth of the wolffian duct contacts the metanephric mesenchyme and induces it to convert to an epithelium. These epithelial cells aggregate to form an s-shaped body that will become the nephron. The induced mesenchyme stimulates the ureteric bud to branch and proliferate. It also attracts endothelial cells to colonize one pole of the s-shaped body to form the glomerulus. We will study the process of conversion from mesenchyme to epithelia by identifying the master genes that are responsible for this phenotype change. Many of these genes are transcription factors, and we identified new prostate specific homeo box genes and will be studying their role in prostate development. We are generating cell lines from mesenchyme and ureteric bud to study their interaction in vitro. A recently converted mesenchymal cell line was found to produce a mitogen and a chemoattractant for endothelial cells and is providing a source for identification of this molecule so critical for angiogenesis of the glomerulus. Polycystic kidney disease is associated with a developmental defect in targeting of the Na,K ATPase as well as by defective extracellular matrix. Cell lines from a murine model of this disease are used to study the cell matrix interactions with an aim at identification of a cellular defect in the disease. Using the powerful method of targeted gene disruption, we have identified a critical gene which when deleted, leads to renal agenesis. This gene is expressed in the tips of the ureteric bud and is a receptor of the tyrosine kinase superfamily. We will aim to study the role of this gene in mesenchyme ureter interaction. A program project grant will increase the interaction among these investigators and lead to even more collaboration facilitating the identification of many important genes needed for correct formation of the kidney and prostate.
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