Mechanisms in Wilms Tumorigenesis

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Wilms tumor is an embryonal kidney cancer of children that has been linked to molecular genetic abnormalities on the short arm of chromosome 11. This tumor is associated with anomalies in the urogenitary system and a shared genetic origin has become evident from the cloning and characterization of the WT1 locus by ourselves and others. WT1 is restricted in expression to the condensing metanephric mesenchyme or developing glomeruli. Thus it must respond to induction signals following interaction of the metanephric mesenchyme and the epithelial ureteric bud and likely regulate the expression of other genes involved in differentiation and morphogenesis. The long term objective of this project is to determine how the WT1 regulates this process by identifying WT1-target genes and defining their role in nephrogenesis and tumorigenesis. These objectives will be achieved by pursuing the following specific aims. To test the hypothesis that WT1 both activates and represses target genes to regulate nephrogenesis in Aim one we will characterize genes identified as potential WT1 targets from GeneChip analyses by studying their promoters, examining their expression in Wilms tumors and during nephrogenesis in vitro and in vivo. In aim two we will use chromatin precipitation to identify genes that are direct transcriptional targets for WT1. In aim three we will modulate WT1 and p53 expression in a Wilms tumor cell line and determine effects on transcript profiles. We will also develop kidney specific cDNA arrays and methods for specifically ablating selective transcripts. The proposed studies promise to provide new insights into the role of WT1 as a transcriptional regulator and to lead to the identification of novel genes involved in nephrogenesis and Wilms tumorigenesis.