Gonad function and sexual differentiation. As shown, several major gene products influence the formation of the bipotential gonad (light gray), the development of the ovary (white), and the development of the testis (dark gray). SF1 is a central player in the bipotential gonad, being regulated by WT1, LHX9, and M33 (CBX2), and at other steps in gonadal differentiation. In XY gonads, SRY functions in a short window in pre-Sertoli cells to up-regulate the transcription of SOX9 that is already expressed at low levels through the action of SF1. This higher SOX9 expression then suppresses SRY in a negative feedback loop and also up-regulates itself through the combined actions of SF1 and SOX9 on the SOX9 promoter. SOX9 also up-regulates FGF9 that signals back through FGFR2 to maintain/increase SOX9 expression. The ovarian differentiation pathway involves RSPO1 increasing the signaling of WNT4, which up-regulates β-catenin. β-catenin acts to up-regulate WNT4 and other proteins such as FST. The testis pathway appears to mainly antagonize this pathway through decreasing β-catenin levels. Likewise, β-catenin antagonizes the testis pathway by destabilizing SOX9.
