Congenital abnormalities of the kidney and urinary tract (CAKUT) are among the most common birth defects in humans. Many of them result from alterations in the normal processes of ureteric bud induction, growth, and branching during the development of the ureter and the renal collecting duct system. These events are controlled, in part, by signaling networks that include secreted growth factors, cell-surface tyrosine kinase receptors, multiple intracellular signaling pathways, and negative feedback mechanisms that keep the signaling networks in balance. GDNF is a mesenchymally-derived growth factor that signals to the ureteric bud epithelium via the Ret receptor tyrosine kinase and the co-receptor Gfr11. In mouse models, GDNF signaling plays a major role in ureter and kidney development, and in humans, RET and GDNF mutations are associated with renal agenesis. Ret activates several intracellular mechanisms, including the Erk MAP kinase pathway, and the response to Ret is controlled through feedback regulation by the intracellular protein Sprouty1. While Sprouty1 is thought to act primary on the Erk MAP kinase pathway, its mechanism is not well understood. However, it is clear that the negative feedback provided by Sprouty1 is critical, as its absence leads to multiple and ectopic ureters, hydroureter, multiplex kidneys with abnormal branching of collecting ducts, and renal cysts. This proposal focuses on the tyrosine kinase signaling networks that control the normal outgrowth of the ureteric bud to form a single and correctly positioned ureter, and then regulate its complex patterns of growth and branching during kidney development. Using the mouse as a model system, we employ a variety of genetic approaches to investigate three related issues. First, we examine the mechanism by which Sprouty1 prevents ureteric bud cells from over-responding to GDNF and other growth factors such as FGFs, and how its absence leads to malformations and cysts in the ureteric bud-derived epithelium. Next, we investigate the unexpected finding that ureters and kidneys can sometimes develop to an advanced stage in mice completely lacking GDNF or Ret, when the negative regulation provided by Sprouty1 is also removed. This suggests that a balance between positive stimuli and negative feedback is perhaps more important than the specific effects of any one growth factor. It also implies that other growth factors that signal through different tyrosine kinase receptors must overlap, to a large degree, with GDNF in its ability to promote and pattern growth and branching of the ureter and collecting ducts. We therefore investigate the roles of several candidates, including fibroblast growth factors (FGFs) and hepatocyte growth factor (HGF), in these processes. This proposal will advance the field by providing a deeper understanding of the multilayered control mechanisms that mediate development of a normal ureter and kidney, and may suggest new ways to prevent or treat CAKUT. Among the most common types of birth defects are those affecting the kidneys and urinary tract. These include abnormalities causing urinary tract obstruction, as well as those that reduce the size and function of the kidney and can lead to hypertension. By identifying the genes and proteins that control the growth of the ureter and kidney from a small group of cells to a complex organ, it may eventually be possible to prevent or repair such birth defects.
