NUCLEAR RECEPTOR STEROIDOGENIC FACTOR-1 REGULATES THE MULLERIAN-INHIBITING SUBSTANCE GENE - A LINK TO THE SEX DETERMINATION CASCADE

Normal mate sex differentiation requires that Sertoli cells in the embryonic testes produce Mullerian inhibiting substance (MIS), a TGF beta-like hormone that causes Mullerian duct regression. In primary Sertoli cells, the orphan nuclear receptor, steroidogenic factor 1 (SF-1), regulates the MIS gene by binding to a conserved upstream regulatory element. In heterologous (HeLa) cells, MIS gene activation by SF-1 requires removal of the SF-1 ligand-binding domain, implicating a Sertoli cell-specific ligand or cofactor. Finally, the sexually dimorphic expression of SF-1 during development coincides with MIS expression and Mullerian duct regression. We propose that SF-1 regulates MIS in vivo and participates directly in the process of mammalian sex determination.