Male-to-Female Sex Reversal in Mice Lacking Fibroblast Growth Factor 9

Abstract

Fgfs direct embryogenesis of several organs, including the lung, limb, and anterior pituitary. Here we report male-to-female sex reversal in mice lacking Fibroblast growth factor 9 (Fgf9), demonstrating a novel role for FGF signaling in testicular embryogenesis. Fgf9(-/-) mice also exhibit lung hypoplasia and die at birth. Reproductive system phenotypes range from testicular hypoplasia to complete sex reversal, with most Fgf9(-/-) XY reproductive systems appearing grossly female at birth. Fgf9 appears to act downstream of Sry to stimulate mesenchymal proliferation, mesonephric cell migration, and Sertoli cell differentiation in the embryonic testis. While Sry is found only in some mammals, Fgfs are highly conserved. Thus, Fgfs may function in sex determination and reproductive system development in many species.

Time course of female‐to‐male sex reversal in 38,XX fetal and postnatal pigs

“…In addition, peritubular myoid cells which originate from mesonephric cells and are specific of testicular differentiation were identified in gonads of the isx pigs described here. Recently, Fgf9Ϫ/Ϫ mice exhibiting phenotypes ranging from testicular hypoplasia to complete male to female sex reversal have been obtained (Colvin et al, 2001). These findings showed that Fgf9 can regulate, directly or indirectly Sertoli cell differentiation.…”

Functional evolutionary history of the mouse Fgf gene family

“…Fgf10 is critical for epithelial-mesenchymal interactions necessary for the development of epithelial components of multiple organs (Min et al, 1998;Sekine et al, 1999;Ohuchi et al, 2000;Sakaue et al, 2002). Fgf9 and Fgf18 have essential roles in the development of mesenchymal components of multiple organs (Colvin et al, 2001a, 2001b, Ohbayashi et al, 2002Liu et al, 2002;Usui et al, 2004). In contrast, Fgf15 knockout mice die at variable times during embryonic and postnatal stages of development.…”

The incomplete inactivation of Fgf8 in the limb ectoderm affects the morphogenesis of the anterior autopod through BMP‐mediated cell death

“…The single targeted deletion of Fgf4, Fgf9, or Fgf17 had no consequences for limb development indicating that other Fgf family members, particularly Fgf8, provide sufficient FGF signaling for normal limb development (Moon and Capecchi, 2000;Xu et al, 2000;Colvin et al, 2001;Sun et al, 2002). In contrast, the conditional elimination of Fgf8 from the limb ectoderm, which has been performed with three different Cre lines, resulted in hypoplastic limbs whose phenotype depended on the specific Cre line used (Lewandoski et al, 2000;Moon and Capecchi, 2000;Boulet et al, 2004).…”