title: 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.
authors.affiliation: Human Molecular Genetics laboratory, Prince Henry's Institute of Medical Research, Monash Medical Centre, Melbourne 3168, Australia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bagheri-Fam
authors.forename: Helena
authors.initials: H
authors.lastname: Sim
authors.forename: Pascal
authors.initials: P
authors.lastname: Bernard
authors.forename: Irumini
authors.initials: I
authors.lastname: Jayakody
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Gerd
authors.initials: G
authors.lastname: Scherer
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Harley
mesh_terms: D000818:Animals; D012734:Disorders of Sex Development; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000502:physiology; D006066:Gonads / Q000166:cytology / Q000196:embryology; D006609:High Mobility Group Proteins / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000502:physiology*; D055758:SOX9 Transcription Factor; D012708:Sertoli Cells / Q000166:cytology / Q000502:physiology; D019849:Sex Determination Processes; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
chemical_list: C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D006609:High Mobility Group Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D014157:Transcription Factors; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2