Development of the kidney is regulated in part by reciprocal inductive interactions between the ureteric bud and metanephric mesenchyme. The receptor tyrosine kinase RET and its ligand glial cell line derived neurotrophic factor (GDNF) are components of a signal transduction pathway that is required for the normal development of the ureter and collecting duct system. However, little is known about the mechanisms that regulate the expression of these two genes, or about the specific biological effects of GDNF/RET signaling in ureteric bud cells. These issues will be investigated through a studies involving: transgenic manipulation of gene expression in the developing mouse kidney; analysis of RET and GDNF regulatory DNA elements; chimeric studies of the developmental potential of mutant cells; and manipulation of kidney development in organ cultures. To understand the consequences of such inductive events, it is necessary to know the normal developmental fate of specific cell populations, yet our knowledge of cell lineages in the kidney is only rudimentary. A novel genetic approach will be used to permanently mark and trace the descendants of cell populations that express RET, GDNF and other genes at specific times in development. The Wnt family of secreted glycoproteins is also important for kidney development, the Axin gene has been found to negatively regulate a Wnt signal transduction pathway. Axin has been directly implicated in kidney development because Fused, a mutant allele of Axin, causes renal agenesis and other urogenital defects in mutant mice. The role of Axin in kidney development will be investigated by analyzing the excretory system defects in Fused mutant embryos, in vivo and in organ culture. Other studies will test the ability of wild type Axin, or a dominant- negative form of Axin to interfere with kidney development when expressed in developing kidney using transgenic techniques. In addition to the basic developmental biology of renal organogenesis, these studies should provide insight into the potential roles of the GDNF/RET and Wnt signal transduction pathways in human renal developmental defects.
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