While GDNF signaling through the Ret receptor tyrosine kinase is essential for renal development in mice and in humans, the events that occur downstream of Ret to promote ureteric bud (UB) branching morpho- genesis remain largely obscure. This proposal concerns two closely related transcription factors, Pea3 and Erm, which are known targets of FGF signaling in other organs. Our preliminary data indicate that Pea3 and Erm are required for normal ureter and kidney development, and that they function downstream of GDNF/ Ret signaling in this process. However, it is unclear if their role is restricted to the ureteric bud, or whether they also function in the metanephric mesenchyme lineage. Our overall goal is to elucidate the role of these transcription factors in development of the excretory system, and to determine why mutations in Pea3 and Erm lead to renal agenesis and hypodysplasia. We will use a variety of in vivo genetic approaches, together with an organ culture system, to address several questions: In what cell lineage(s) in the developing kidney are these genes required? How is the behavior of individual mutant cells in genetically mosaic kidneys affected by their absence? Is the expression of Pea3 and Erm in the kidney regulated by FGFs as well as by GDNF? What downstream genes do these transcription factors regulate, which might explain their importance for branching morphogenesis? These studies will test a model in which GDNF and FGFs control the expression of Pea3 and Erm, which in turn regulate a """"""""battery"""""""" of effector genes that mediate the effects of these growth factors on branching morphogenesis. Understanding the mechanisms by which Pea3 and Erm promote UB growth and branching, when activated by specific growth factors, is not only an important basic problem in the genetic control of organogenesis. It also has important clinical implications, as renal agenesis, hypodysplasia and ureteral defects are common birth defects, which can often be attributed to abnormalities in the development of the UB. The pattern of branching morphogenesis of this epithelial tissue not only determines the structure of the collecting system - it also influences the number of nephrons, which is quite variable in humans, and is thought to influence the rate of progression of renal diseases and the development of hypertension. It is therefore possible that mutations in Pea3 and Erm may contribute to renal developmental defects in humans. ? ? ?
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