About 20 million Americans are affected each year by kidney and urological diseases. The societal and monetary cost of kidney disease is substantial. Our interest lies in elucidating the molecular and cellular mechanisms that establish a physiological competent organ during fetal life. Simply put, how do nephrons form? A variety of experiments over the last fifty years have highlighted the importance of cell-cell interactions. In these, the ureteric bud, which gives rise to the collecting duct network of the mature kidney, induces mesenchymal precursors to transform into small epithelial tubules, the renal vesicles. The mesenchyme in turn stimulates branching growth of the ureteric epithelium leading to new rounds of tubule induction. Several members of the Wnt-family of secreted glycoproteins are expressed in different positions along the proximo-distal (cortical to medullary) axis of the ureteric epithelium. The proximal boundary of Wnt15 expression is positioned just beneath the branch tips while that of Wnt7b is more distal and extends into the ureter. We have generated mutant alleles that allow the conditional removal of Wnt l5 and Wnt7b activities and we will utilize these genetic tools to characterize the renal functions of these Wnts. One class of Wnt signal utilizes a beta-catenin:Lef/TCF transcriptional complex. B-catenin is also a possible downstream mediator of the action of polycystic kidney disease genes. We have developed a mouse model that removes beta-catenin activity from collecting duct epithelia. We will explore the mechanism underlying the resulting cystic phenotype. Wnt4 plays a key role in the induction of renal vesicles. Subsequent morphogenesis and patterning establishes a segmental organization that is critical to normal renal function whereby various channels, transporters and pumps are expressed at specific positions along the length of the nephron. We propose to undertake large-scale gene-expression analysis with libraries of transcriptional regulators and renal tubule specific cDNAs identified by transcriptional profiling on oligonucleotide microarrays to both characterize the process of renal tubule development and to identify potential regulatory factors of this process.
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