Summary in humans, germiine mutations of the WT-7 tumor suppressor gene are associated with both Wiims’ tumors and urogenital malformations. To develop a model system for the molecular analysis of urogenital deveiopment, we introduced a mutation into the murine WT. 7 tumor suppressor gene by gene targeting in embryonic stem cells. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos revealed a failure of kidney and gonad development. Specifically, at day 11 of gestation, the ceils of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the Woiffian duct, and the inductive events that lead to formation of the metanephric kidney did not occur. in addition, the mutation caused abnormal development of the mesotheiium, heart, and lungs. Our results establish a crucial role for WT. 1 in early urogenital development. introduction

Urogenital development in mammals proceeds in three stages that are ail characterized by the induction of a mesenchymal to epithelial transformation (reviewed by Saxen, 1987). in the first two stages, the transient pronephros and mesonephros form along the urogenital ridge, where nephrogenic mesenchyme is induced by the adjacent nephric duct to form nephric tubules. in the third stage, the definitive kidney forms as a result of subsequent reciprocal interactions between the metanephric biastema and the