WT1 is a developmentally regulated kidney zinc finger transcription factor which is inactivated in the germline of children predisposed to Wilm's tumor. Both loss of WT1 and overexpression of WT1 lead to apoptosis of renal stem cells critical to kidney development and function. Although WT1 is known to bind to a GC-rich consensus sequence and to repress the activity of promoters with which it interacts, there remain a paucity of genes identified as physiological WT1 targets. WT1 is alternately spliced but no specific function has been assigned to the different splice forms that are prevalent. Thus, while WT1 is a paradigm for a tissue-specific tumor suppressor, little is known about its function, regulatory pathways, and role in tissue differentiation. Dr. Haber proposes to analyze a candidate target gene he has identified, the cell cycle kinase inhibitor p21, and to identify other potential target genes using an inducible cell system. He also aims to identify WT1-binding proteins by two hybrid and immunological approaches. Two model systems are proposed for use to study the functional interactions with candidate target genes and binding proteins. The first system is based on a kidney stem cell assay and the second on a hematopoietic model in which WT1 appears to contribute to development arrest and leukemogenesis. Finally, Dr. Haber proposes to seek other potential Wilm's tumor genes using his collection of normal/tumor pairs of DNAs and the RDA approach developed by Lisitsyn and Wigler.
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