Regulation of Cell Signaling and Branching morphogenesis

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Branching morphogenesis, defined as the growth and branching of epithelial tubes, is fundamental to the formation of the vascular system, nervous system, kidney, lung, pancreas, mammary and salivary glands. During branching morphogenesis groups of epithelial cells form branches that have defined branch patterns, length, diameter, shape and spacing and undergo numerous cellular activities. How cells regulate multiple cellular events through a single receptor is not well understood. The activation of the Ret receptor tyrosine kinase by its ligand Glial cell-line derived neurotrophic factor (Gdnf) leads to multiple cellular events in the kidney and represents and attractive model to answer this question. How Gdnf/Ret signaling is regulated and how it alters the behavior of epithelial cells to undergo the many distinct cellular processes is not clear. It is suspected activation of distinct signaling pathways may determine the biological output. We and others have shown that ß-catenin is essential for branching morphogenesis in numerous organ systems. In the cell ß-catenin is involved in cell adhesion by binding to adherens junctions or is in a cytoplasmic/nuclear component that acts to transduce Wnt signals. Recent studies have demonstrated a novel Ret kinase/ß-catenin signaling pathway in multiple endocrine neoplasia's and data from my lab strongly supports an essential role for this novel pathway. To address this possibility I propose, to (1) examine if ß-catenin acts upstream of Ret signaling by determining if it has a direct effect on Gdnf expression (and other genes known to regulate Gdnf expression) and (2) to ask whether ß-catenin is activated in response to Gdnf/Ret signaling and regulates distinct genes and biological functions. These findings could be applied to all developing, mature, and diseased organ systems as the signaling pathway and genes identified here are likely fundamental processes. Further Gdnf/Ret signaling is essential for the development and maintenance of the urogential and nervous systems. Identifying a novel Ret/ß-catenin signaling pathway could provide novel molecular approaches for repair in the nervous, kidney and reproductive systems.