Adressing the function of the Wilms tumor gene 1 (Wt1) by conditional inactivation in the mouse

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The Wilms tumor protein WT1 is an essential factor for kidney development. In humans, mutations in WT1 lead to Wilms tumor, a pediatric kidney cancer as well as to developmental anomalies affecting the urogenital tract. Inactivation of Wt1 in mice causes multiple organ defects including anomalies of gonads, heart, spleen, retina, the olfactory system and agenesis of the kidneys. Deeper insights into the functional properties of WT1 during the different phases of development are hampered by the early lethality of Wt1 knockout embryos. We have therefore generated a conditional Wt1 allele that allows the inactivation of Wt1 in a temporally and spatially controllable manner. Here we propose two different experiments. First we want to explore the molecular mechanism by which WT1 affects development, differentiation and maintenance of podocytes. The latter are highly specialized cells that form the basis for blood filtration in the glomerulus of the kidney. Wt1 will be deleted specifically in podocytes either in late embryonic development or in an inducible manner in different stages of adulthood. Second, preliminary data suggest a novel role for WT1 in very early development. We hypothesize that “maternal” WT1 is required in order to provide an environment for the developing embryo to execute the first cleavages. This hypothesis will be tested by different experimental strategies including microarrays and utilization of the conditional Wt1 knockout mouse.