Testis Determination Requires a Specific FGFR2 Isoform to Repress FOXL2

Endocrinology. 2017 Nov 1;158(11):3832-3843. doi: 10.1210/en.2017-00674.

Abstract

Male sex determination in mammals relies on sex determining region Y-mediated upregulation of sex determining region-box 9 (SOX9) expression in XY gonads, whereas Wnt family member (WNT)/R-spondin 1 signaling and forkhead box L2 (FOXL2) drive female sex determination in XX gonads. Fibroblast growth factor (FGF) 9 signaling ensures sustained SOX9 expression through repression of one of the ovarian pathways (WNT signaling), whereas the significance of FGF-mediated repression of the FOXL2 pathway has not been studied. Previously, we demonstrated that FGFR2 is the receptor for FGF9 in the XY gonad. Whether a specific isoform (FGFR2b or FGFR2c) is required was puzzling. Here, we show that FGFR2c is required for male sex determination. Initially, in developing mouse embryos at 12.5 to 13.5 days postcoitum (dpc), XY Fgfr2c-/- gonads appear as ovotestes, with SOX9 and FOXL2 expression predominantly localized to the posterior and anterior gonadal poles, respectively. However, by 15.5 dpc, XY Fgfr2c-/- gonads show complete male-to-female sex reversal, evident by the lack of SOX9 and ectopic expression of FOXL2 throughout the gonads. Furthermore, ablation of the Foxl2 gene leads to partial or complete rescue of gonadal sex reversal in XY Fgfr2c-/- mice. Together with previous findings, our data suggest that testis determination involves FGFR2c-mediated repression of both the WNT4- and FOXL2-driven ovarian-determining pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Down-Regulation / genetics
  • Embryo, Mammalian
  • Embryonic Development / genetics
  • Female
  • Forkhead Box Protein L2 / genetics*
  • Gene Expression Regulation, Developmental
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Ovary / embryology
  • Ovary / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • Receptor, Fibroblast Growth Factor, Type 2 / physiology*
  • Sex Determination Processes / genetics*
  • Testis / embryology*
  • Testis / metabolism
  • Wnt4 Protein / genetics

Substances

  • Forkhead Box Protein L2
  • Foxl2 protein, mouse
  • Protein Isoforms
  • Wnt4 Protein
  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2