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Wilms tumor gene, Wt1, is abundantly expressed in testis Sertoli cells. Our recent study demonstrated that Wt1 is involved in spermatogenesis by regulating Sertoli cell polarity. In the present study, we found that Wt1 is also required for steroidogenesis in Leydig cells and that deletion of the Wt1 gene resulted in defects in testosterone biosynthesis and downregulation of steroidogenic gene expression, including cytochrome P450 side-chain cleavage (P450scc), steroidogenic acute regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase I (3beta-HSD), and cytochrome P450 17A1 (Cyp17a1). The expression of LHR was significantly decreased in Wt1(-/flox); Cre-ERTM testes after tamoxifen induction, whereas the luteinizing hormone level in serum was unchanged. Further studies revealed that desert hedgehog (Dhh) expression was regulated by Wt1 in Sertoli cells and that its expression was significantly reduced in Wt1-deficient testes. In vitro study demonstrated that the defect in testosterone production and decreased expression of several steroidogenic genes in Wt1-deficient testis explants was partially rescued by smoothened agonist (SAG), a hedgehog pathway agonist. These results indicate that Wt1 is most likely involved in Leydig cell steroidogenesis by regulating the expression of paracrine factors in seminiferous tubules. Dhh probably had important roles in this process, but we could not exclude the possibility that other factors were also required for Leydig cell steroidogenesis. Loss of Wt1 leads to downregulation of paracrine factors, which in turn causes a decrease in steroidogenic enzyme expression and reduces testosterone production in Leydig cells. The results of this study further confirm that the cross talk between Sertoli cells and Leydig cells has important roles in Leydig cell steroidogenesis.