Loss of Fgfr2 leads to partial XY sex reversal

Abstract

In mammals, sex is determined in the bipotential embryonic gonad by a balanced network of gene actions which when altered causes disorders of sexual development (DSD, formerly known as intersex). In the XY gonad, presumptive Sertoli cells begin to differentiate when SRY up-regulates SOX9, which in turn activates FGF9 and PGDS to maintain its own expression. This study identifies a new and essential component of FGF signaling in sex determination. Fgfr2 mutant XY mice on a mixed 129/C57BL6 genetic background had either normal testes, or developed ovotestes, with predominantly testicular tissue. However, backcrossing to C57BL6 mice resulted in a wide range of gonadal phenotypes, from hypoplastic testes to ovotestes with predominantly ovarian tissue, similar to Fgf9 knockout mice. Since typical male-specific FGF9-binding to the coelomic epithelium was abolished in Fgfr2 mutant XY gonads, these results suggest that FGFR2 acts as the receptor for FGF9. Pgds and SOX9 remained expressed within the testicular portions of Fgfr2 mutant ovotestes, suggesting that the Prostaglandin pathway acts independently of FGFR2 to maintain SOX9 expression. We could further demonstrate that double-heterozygous Fgfr2/Sox9 knockout mice developed ovotestes, demonstrating that both Fgfr2 and Sox9 can act as modifier intersex genes in the heterozygous state. In summary, we provide evidence that FGFR2 is important for male sex determination in mice, thereby rendering human FGFR2 a candidate gene for unsolved DSD cases such as 10q26 deletions.

The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation

“…Conditional deletion of Fgfr2 in mouse embryonic gonads confirmed the distinct roles of FGF9 in Sertoli cell proliferation and differentiation (Bagheri-Fam et al, 2008;Kim et al, 2007).…”

FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands

“…Fgfr2 deletion leads to decreased Sox9 expression in the distal lung bud epithelium (Abler et al, 2009) and FGFs enhance Sox9 expression through the MAP kinase pathway in chondrogenesis (Abler et al, 2009). During Sertoli cell differentiation and testis development, Fgfr2 is important for the maintenance of Sox9 expression and Sox9 is required for Fgfr2 nuclear localization (Bagheri-Fam et al, 2008). Sox9 and Fgf10-Fgfr2b form a feedforward loop in the pancreatic progenitor cell niche that maintains pancreatic organ identity.…”

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).…”