WILMS-TUMOR-1 AND DAX-1 MODULATE THE ORPHAN NUCLEAR RECEPTOR SF-1 IN SEX-SPECIFIC GENE-EXPRESSION

Products of steroidogenic factor 1 (SF-1) and Wilms' tumor 1 (WT1) gen es are essential for mammalian gonadogenesis prior to sexual different iation. In males, SF-1 participates in sexual development by regulatin g expression of the polypeptide hormone Mullerian inhibiting substance (MIS). Here, we show that WT1 -KTS isoforms associate and synergize w ith SF-1 to promote MIS expression. In contrast, WT1 missense mutation s, associated with male pseudohermaphroditism in Denys-Drash syndrome, fail to synergize with SF-1. Additionally, the X-linked, candidate do sage-sensitive sex-reversal gene, Dax-1, antagonizes synergy between S F-1 and WT1, most likely through a direct interaction with SF-1. We pr opose that WT1 and Dax-1 functionally oppose each other in testis deve lopment by modulating SF-1-mediated transactivation.