Ovotesticular disorders of sex development in FGF9 mouse models of human synostosis syndromes
| Autor: | Stefan Bagheri-Fam, Brittany Croft, Lingyun Tang, Zhenhua Ming, Peter Koopman, Vincent R. Harley, Liang Zhao, Anthony Daniel Bird, Keiichi Akita, Masayo Harada, Zhugang Wang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Fibroblast Growth Factor 9
Male medicine.medical_specialty Male sex determination Mutation Missense SOX9 Biology 010402 general chemistry 01 natural sciences Mice 03 medical and health sciences FGF9 Internal medicine Genetics medicine Animals Humans Disorders of sex development Receptor Fibroblast Growth Factor Type 2 Gonads Molecular Biology Genetics (clinical) 030304 developmental biology Phenocopy 0303 health sciences Sexual Development Gene Expression Regulation Developmental SOX9 Transcription Factor General Medicine Sex Determination Processes Sex reversal medicine.disease Phenotype Ovotesticular Disorders of Sex Development 0104 chemical sciences Disease Models Animal stomatognathic diseases Endocrinology Synostosis Female Development of the gonads |
| Zdroj: | Human Molecular Genetics. 29:2148-2161 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddaa100 |
| Popis: | In mice, male sex determination depends on FGF9 signalling via FGFR2c in the bipotential gonads to maintain the expression of the key testis gene SOX9. In humans, however, while FGFR2 mutations have been linked to 46,XY disorders of sex development (DSD), the role of FGF9 is unresolved. The only reported pathogenic mutations in human FGF9, FGF9S99N and FGF9R62G, are dominant and result in craniosynostosis (fusion of cranial sutures) or multiple synostoses (fusion of limb joints). Whether these synostosis-causing FGF9 mutations impact upon gonadal development and DSD etiology has not been explored. We therefore examined embryonic gonads in the well-characterized Fgf9 missense mouse mutants, Fgf9S99N and Fgf9N143T, which phenocopy the skeletal defects of FGF9S99N and FGF9R62G variants, respectively. XY Fgf9S99N/S99N and XY Fgf9N143T/N143T fetal mouse gonads showed severely disorganized testis cords and partial XY sex reversal at 12.5 days post coitum (dpc), suggesting loss of FGF9 function. By 15.5 dpc, testis development in both mutants had partly recovered. Mitotic analysis in vivo and in vitro suggested that the testicular phenotypes in these mutants arise in part through reduced proliferation of the gonadal supporting cells. These data raise the possibility that human FGF9 mutations causative for dominant skeletal conditions can also lead to loss of FGF9 function in the developing testis, at least in mice. Our data suggest that, in humans, testis development is largely tolerant of deleterious FGF9 mutations which lead to skeletal defects, thus offering an explanation as to why XY DSDs are rare in patients with pathogenic FGF9 variants. |
| Databáze: | OpenAIRE |
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