Figure 1

Molecular and genetic events in mammalian sex determination. Genes in the female pathway repress Sox9; genes in the male pathway express it. “The bipotential genital ridge is established by genes including Wt1 and Sf1, the early expression of which might also initiate that of Sox9 in both sexes. β-catenin can begin to accumulate as a response to Rspo1-Wrt4 signaling at this stage. In XX supporting cell precursors, β-catenin levels could accumulate sufficiently to repress SOX9 activity, either through direct protein interactions leading to mutual destruction, as seen during cartilage development, or by a direct effect on Sox9 transcription. However, in XY supporting cell precursors, increasing levels of SF1 activate Sry expression and then SRY, together with SF1, boots Sox9 expression. Once SOX9 levels reach a critical threshold, several positive regulatory loops are initiated, including autoregulation of its own expression and formation of feed-forward loops via FGF9 or PGD2 signaling. If SRY activity is weak, low or late, it fails to boost Sox9 expression before β-catenin levels accumulate sufficiently to shut it down. At later stages, FOXL2 increases, which might help, perhaps in concert with ERs, to maintain granulosa (follicle) cell differentiation by repressing Sox9 expression. In the testis, SOX9 promotes the testis pathway, including Amh activation, and it also probably represses ovarian genes, including Wnt4 and Foxl2. However, any mechanism that increases Sox9 expression sufficiently will trigger Sertoli cell development, even in the absence of SRY” (Sekido et al. 2009).