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Testis Determination Requires a Specific FGFR2 Isoform to Repress FOXL2
Stefan Bagheri-Fam1,2, Anthony D Bird1, Liang Zhao3
1Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Monash Medical Centre, Melbourne, Victoria 3168, Australia.
Endocrinology
|September 23, 2017
Summary
Fibroblast growth factor receptor 2c (FGFR2c) is essential for male sex determination in mammals. Loss of FGFR2c causes male-to-female sex reversal by failing to repress ovarian pathways like FOXL2.
Area of Science:
- Mammalian sex determination
- Molecular genetics
- Developmental biology
Background:
- Male sex determination involves SOX9 upregulation in XY gonads.
- Female sex determination is driven by WNT/R-spondin 1 and FOXL2 in XX gonads.
- Fibroblast growth factor (FGF) 9 signaling maintains SOX9 expression and represses WNT signaling, but its role in repressing FOXL2 is unknown.
Purpose of the Study:
- To investigate the role of specific fibroblast growth factor receptor 2 (FGFR2) isoforms in male sex determination.
- To determine if FGFR2c is required for repressing ovarian pathways, specifically FOXL2, during male gonad development.
Main Methods:
- Analysis of XY Fgfr2c knockout (Fgfr2c-/-) mouse embryos at different developmental stages (12.5-15.5 days postcoitum).
- Immunohistochemical analysis of SOX9 and FOXL2 expression in gonads.
- Genetic ablation of the Foxl2 gene in XY Fgfr2c-/- mice to assess rescue effects.
Main Results:
- XY Fgfr2c-/- gonads initially developed as ovotestes but by 15.5 dpc showed complete male-to-female sex reversal.
- Sex reversal was characterized by loss of SOX9 and ectopic FOXL2 expression throughout the XY gonads.
- Ablation of Foxl2 partially or completely rescued the gonadal sex reversal in XY Fgfr2c-/- mice.
Conclusions:
- FGFR2c is required for male sex determination in mammals.
- Testis determination involves FGFR2c-mediated repression of both WNT4 and FOXL2 ovarian-determining pathways.
- FGFR2c signaling is critical for preventing female development in XY gonads.
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