ESPE Yearbook of Paediatric Endocrinology

Hum Mol Genet. 2020 Aug 3;29(13):2148–2161. doi: doi:10.1093/hmg/ddaa100. https://www.ncbi.nlm.nih.gov/pubmed/32452519

This study explores the hitherto unknown role of FGF9 in human testis development. The authors use two mouse models that phenocopy the skeletal defects of dominant FGF9 mutations that cause skeletal synostosis syndromes in humans. The results show partially reversible disrupted testis development in male mice.

The loss of FGF9 signalling in Fgf9^−/− mice leads to disrupted Sertoli cell differentiation and up-regulation of ovary-promoting genes such as Wnt4 and Foxl2 with subsequent male-to-female sex reversal. Although loss-of-function mutations in its receptor FGFR2 have been associated with disturbed gonadal development in 46,XY individuals, pathogenic FGF9 mutations have never been identified in series of patients who have 46,XY DSD. FGF9^S99N and FGF9^R62G cause human synostosis syndromes in a dominant fashion. However, the gonadal phenotype in these syndromes has not been described. Here, the Fgf9^S99N and Fgf9^N143T mouse models, that phenocopy the skeletal defects seen with the respective human mutations are used to study the impact of these variants on mouse testis development. The paper offers a series of comprehensive experiments that are presented and analysed in detail. Paradoxically, the mutants exert gain-of function effects in skeletal tissue and loss-of-function effects in the gonad, and the experiments offer mechanistic insight into these intriguing differential effects. In bone, Fgf9 and its ligands are often expressed in non-overlapping regions, suggesting that diffusion of Fgf9 is required before it can exert its activity. The mutants that cause synostosis have been suggested to act through hyperdiffusion, as they have been shown to disrupt Fgf9 dimerisation. In the testis, a loss-of-function effect is observed, due to disrupted binding of the Fgf9 mutant to its receptor.

Overall, the experiments demonstrate a hypomorphic and transient delay in testis development in mice due to reduced Sertoli cell proliferation, and highlight at the same time the importance of the genetic background. Parallels and differences with the human situation are clearly outlined. In conclusion, this basic research paper elegantly illustrates how mouse models can further progress our understanding of human sex development even in the absence of informative human case reports.