Development of the kidney begins when the ureteric bud invades the metanephric mesenchyme and induces it to change to an epithelial phenotype. The induced mesenchyme then induces the ureteric bud to branch. This reciprocal induction is mediated by a cascade of known and we suspect many more unknown molecules. The major aim of our Program is to identify new molecules that are critical in this process. Members of this PPG have already identified new genes that are critical nephrogenesis, the c-ret oncogene and its ligand GDNF; when either is deleted, renal agenesis develops. The same group, led by Dr. Constantini found that mutation in a new gene termed Axin, the product of the fused locus in mice also leads to severe kidney dysplasia, and much excitement was generated when they discovered that this gene is a critical component of the wnt pathway, a pathway known to be critical for urogenital development. A recent study by another members of this PPG (Mendelsohn) found that one retinoic acid receptor (RAR beta 2) is highly expressed in the stromal cells and deletion of this gene leads to renal agenesis. Dr. J Barasch has produced a ureteric bud cell line whose supernatant can rescue mesenchyme from apoptosis and whose membrane induce the rescued mesenchyme to covert to tubular epithelia. He has already purified growth factors from these supernatants and generated inhibitory monoclonal antibodies against the inducing membranes. Dr. Al-Awqati generated a monoclonal antibody that inhibited branching morphogenesis and has purified its antigen, a membrane protein expressed in induced mesenchyme but not in the adult kidney. The cDNA shows that is a new basal protein likely to be a receptor for another protein in the extracellular matrix. Another antibody inhibited angiogenesis in the developing kidney and when its antigen was purified and cloned, it was found to be expressed in mesangial and smooth muscle cells in the adult. These four scientists with complementary expertise will collaborate by using genetic, biochemical and cellular method to examine the structure and function of these new genes and their role in the formation of the three dimensional architecture of the kidney. While it is obvious that congenital renal dysplasias must be caused by mutations in these and other morphogenetic genes, there is evidence that genetically determined differences in the number of functioning nephrons might be at the heart of many kinds of hypertension and perhaps other kidney diseases. Hence, studies of the early stages of kidney development, the stage at which the number of nephrons is determined are likely to have wide clinical implications.
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