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

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.

A study of goat SRY protein expression suggests putative new roles for this gene in the developing testis of a species with long‐lasting SRY expression

“…Nevertheless, regardless of speculation on this somatic role, our results suggest that goat SRY may have functions other than up-regulating SOX9, at least in non-Sertoli somatic cells. As for the second question, as it has been shown in mice that the maintenance of Sox9 expression requires two independent positive feed forward loops, one engaging Fgf9 and Fgfr2 (Kim et al, 2006;Bagheri-Fam et al, 2008;Hiramatsu et al, 2010), and the other Pgds and PGD2 (Wilhelm et al, 2005;Moniot et al, 2009), so we tried to evaluate these pathways in the goat. Of interest, FGFR2 was found to be expressed specifically in differentiating Sertoli cells at the time of SOX9 up-regulation.…”

“…Consequently, the first steps of testis differentiation appear to be straightforward in the mouse: pre-Sertoli cells specifically express SRY that directly activates transcription of the Sox9 gene (Sekido and Lovell-Badge, 2008). Once SOX9 is up-regulated in the Sertoli cells, its expression is maintained by at least two positive feedback loops, one that involves Fgf9 and its receptor Fgfr2 (Kim et al, 2006;Bagheri-Fam et al, 2008;Hiramatsu et al, 2010), and the other which acts through the Pgds gene and its by-product PGD2 (Wilhelm et al, 2005;Moniot et al, 2009). Concomitantly to the maintenance of Sox9 expression, Sry expression declines and then disappears completely after seminiferous cord formation at around 12.5 dpc (Wilhelm et al, 2005).…”

Human SRY inhibits β-catenin-mediated transcription

“…divert gonadal development from the default ovarian determination pathway . However, the recent demonstration that Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination, provided evidence for a crosstalk between male and female gonadal development (Kim et al, 2006b). In XY mice, testis determination is triggered by the transient expression of a single Y-chromosome gene, Sry (sex-determining region on the Y chromosome) whereas in XX females (in the absence of Sry), ovarian development proceeds .…”

La prostaglandine D2

“…L'analyse des gonades des souris invalidées pour le gène L-PGDS indique un défaut de la mise en place des tubules sémi-nifères, confirmant les expériences in vitro précédemment décrites (résultats non publiés). L'activation de cette voie de signalisation est concomitante à la mise en place de la boucle d'autorégu-lation entre Fgf9 et Sox9 contribuant à la surexpression de Sox9 dans la cellule de Sertoli [40].…”