Fgf9 and Wnt4 Act as Antagonistic Signals to Regulate Mammalian Sex Determination

TLDR

WNT and FGF signaling pathways coordinate developmental processes, and in mice Fgf9 and Wnt4 are expressed in both male and female gonads before sex determination, but their interaction with the male sex‑determining gene Sry was previously unclear. The study aims to determine whether FGF9 and WNT4 act as opposing signals that regulate sex determination. Using gain‑ and loss‑of‑function experiments, the authors show that in XY gonads Sry activates a Sox9–Fgf9 feed‑forward loop that up‑regulates Fgf9 and represses Wnt4, establishing the testis pathway. Loss of Fgf9 causes XY sex reversal, while loss of Wnt4 induces testis‑like development in XX gonads and can up‑regulate Fgf9 and Sox9 without Sry, demonstrating that sex determination is governed by antagonism between Fgf9 and Wnt4, with Sry tipping the balance.

Abstract

The genes encoding members of the wingless-related MMTV integration site (WNT) and fibroblast growth factor (FGF) families coordinate growth, morphogenesis, and differentiation in many fields of cells during development. In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination. Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads. However, the relationship between these signals and the male sex-determining gene, Sry, was unknown. We show through gain- and loss-of-function experiments that fibroblast growth factor 9 (FGF9) and WNT4 act as opposing signals to regulate sex determination. In the mouse XY gonad, Sry normally initiates a feed-forward loop between Sox9 and Fgf9, which up-regulates Fgf9 and represses Wnt4 to establish the testis pathway. Surprisingly, loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry. These data suggest that the fate of the gonad is controlled by antagonism between Fgf9 and Wnt4. The role of the male sex-determining switch— Sry in the case of mammals—is to tip the balance between these underlying patterning signals. In principle, sex determination in other vertebrates may operate through any switch that introduces an imbalance between these two signaling pathways.