Fig. 2. WT1 acts at multiple steps during gonad formation and sex determination. WT1(-KTS) variants can transactivate Sf1. Both WT1 and Sf1 are required for survival of the bi-potential gonads. WT1(+KTS) products are necessary for the expression of high levels of the sex-determining gene Sry. Sry directly or indirectly leads to the activation of Sox9, which in turn stimulates the expression of the anti-Mullerian hormone MIS (AMH). Furthermore, WT1(-KTS) can directly transactivate MIS, Dax1 and at least indirectly Wnt-4. Transactivation of the MIS promoter is achieved through the direct interaction of WT1(-KTS) with SF1 protein. This transactivation of the MIS promoter, but also the Dax1 promoter is increased through interaction of WT1 with the LIM-only co-activator FHL2. Dax1, a gene that can interfere with male sexual development is a repressor of the MIS promoter.

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