Analysis of Wilms tumour gene 1 (wt1) regulation and function in zebrafish

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The tumour suppressor gene WT1/wt11 encodes a zinc finger transcription factor whose inactivation leads to Wilms tumour, a pediatric kidney cancer as well as to developmental anomalies concerning the urogenital system. Despite many years of research, mostly in man and mouse, knowledge about the precise physiologic and molecular function of the respective gene-product is scarce. We want to use the teleost fish Danio rerio (zebrafish) as a system to study the regulation and the physiologic role of wt1. The specific goals of this proposal are twofold. First, we want to know how wt1 expression is regulated in zebrafish. This will be analysed by the generation of GFP transgenic fish and subsequent biochemical experiments. The second goal is to elucidate the function of wt1 in development. We want to conduct overexpression and knockdown experiments using morpholinos. Finally, we want to identify molecules that mediate the activity of wt1. For this, knockdown of wt1 function and comparison of gene expression in normal and wt1-knockdown cells will be employed. Given the conservation of developmental processes across species we expect that the results which will be obtained through the experiments outlined here will contribute to the understanding of gene regulation, development and last but not least cancer biology also in higher vertebrates.