Opposing signals regulate sex determination in the bipotential gonad. In both XX and XY gonads at 10.5–11.5 d postcoitum (dpc), Fgf9 transcripts (blue) are detected near the gonadal surface, whereas Wnt4 transcripts (pink) are detected near the gonad mesonephric boundary (). At this time, in the bipotential gonad, there is a balance between these two competing signals. A genetic or environmental switch initiates the male pathway by creating an imbalance between these signals. Sry is activated in the XY gonad, and its expression diverts the XY gonad toward a testis-specific fate. Sry up-regulates Sox9, which has been implicated in the early steps of the male-specific pathway (,). Sox9 then up-regulates Fgf9, and Fgf9 (through FGFR2) maintains Sox9, forming a positive feedback loop in XY gonads (). In this circumstance, the balance between FGF9 and Wnt4 signals is shifted in favor of FGF9, silencing Wnt4 signaling, and the dominance of the male pathway is established. In the absence of a feed-forward loop between SOX9 and FGF9 (e.g., in XX gonads), WNT4 suppresses Fgf9 transcription, initiating the female differentiation pathway.
