The general interest of our laboratory is in the role of cell-cell signaling and signal transduction in renal organogenesis, with emphasis on the Ret receptor tyrosine kinase. Since discovering that Ret is required for kidney development, we have focused on understanding the role of Ret, its ligand GDNF, and downstream signaling pathways and target genes in branching morphogenesis. Our main approach is to generate transgenic, chimeric, knock-in and knock-out mice, to manipulate the expression and/or sequence of proteins in the GDNF/Ret signaling pathway, and then to investigate the effects of these manipulations during development in vivo and in organ explant cultures. Some of the questions currently addressed are: - What changes in the behavior of ureteric bud cells are induced by GDNF/Ret signaling, and how do these events contribute to branching morphogenesis? - Do the expression patterns of GDNF and Ret provide positional information that determines the specific pattern of ureteric bud branching? - What intracellular signaling pathways triggered by GDNF/Ret are important for ureteric bud development, and what target genes are activated or repressed by GDNF/Ret signaling? - What are the developmental functions of these target genes, and how do they mediate the effects of GDNF? - How does GDNF/Ret signaling interact with other signaling pathways (e.g., those activated by FGFs, Wnts, and BMPs) to regulate ureteric bud growth and branching? - What are the properties of stem cells for the ureteric bud and nephron lineages in the developing kidney. Studies of renal branching morphogenesis have been greatly aided by an organ culture system in which the early events of kidney development can be visualized in real time, and we have generated several strains of mice and embryonic stem cell lines that facilitate such studies. We continue to develop new reporter strains of mice that will be useful for visualizing dynamic processes such as cell migration, changes in cell shape and cell division in developing kidneys.