The organogenesis of the kidney depends on the reciprocal inductive interactions between the ureteric bud and the metanephrogenic mesenchyme: the ureteric bud induces the mesenchymal cells to form the nephron, while the mesenchyme induces the ureteric bud to branch and elongate, forming the collecting ducts. While these interactions have been well documented on a phenomenological level, none of the inducers or the receptors involved in these events has previously been identified. We have discovered that the c-ret proto-oncogene, a trans-membrane receptor tyrosine kinase, plays an essential role in kidney development in the mouse. c-ret mRNA is normally expressed in embryonic nephric ducts, in the ureteric bud, and in the tips of the growing ureteric branches, but not in the mesenchyme or its derivatives. Furthermore, mice homozygous for a targeted mutation in the c-ret gene display either complete renal agenesis or hypoplastic dysgenesis, but never develop a normal kidney and die soon after birth. These findings suggest that the ret protein normally serves to transduce an inductive signal derived from the metanephrogenic mesenchyme, which is necessary for the elongation and/or branching of the ureter and its derivatives. We propose to test this hypothesis and to further examine the role of the ret receptor in renal organogenesis. Thus, we will perform a series of embryological and organ culture analyses to characterize the defects in kidney development in c- ret mutant embryos. We will also use transgenic techniques to manipulate the expression pattern of the c-ret gene, and express altered forms of ret protein, in the developing kidney. We will attempt to identify other genes that affect the expression of c-ret, or are themselves affected by ret signal transduction, using various cloned probes as well as several mutant mouse strains displaying defects in renal development. We will determine whether alterations in the expression of the c-ret gene may play a role in polycystic kidney disease, in existing murine models on ret transgenic mice. Finally, we will investigate the distribution of the putative ret ligand, and when the gene for this ligand is identified, will perform transgenic and gene targeting experiments to investigate its function. These studies should provide insight into the normal mechanisms of kidney development, as well as human hereditary defects such as renal agenesis and polycystic kidney disease.
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