Dr Daniel Bird
It is known that the protein 'Fibroblast Growth Factor 9' (Fgf9) is responsible for promoting male testicular development in XY individuals by inhibiting the pro-female signalling pathway known as 'Wnt4/beta-catenin'. Our study found that a particular variant of a protein receptor; Fgfr2c, is responsible for mediating these Fgf9 signals. This was shown by examining gonads from embryonic XY mice lacking Fgfr2c, which developed ovaries rather than testes. We also showed that the pro-testicular activities of Fgfr2c included repression of a second pro-female signalling pathway known as 'Foxl2'. Gonads from embryonic XY mice lacking both Fgfr2c and Foxl2 were often found to be testes, indicating the loss of Foxl2 had 'rescued' testes development.
Centre for Endocrinology and Metabolism
Sex Determination and Gonadal Development
Journal and article title
Though we had suspected the 2c variant of Fgfr2 was involved in testicular development, it had been puzzling why previous analysis of Fgfr2c knockout mice showed no apparent fertility issues in males. However, we found that the genetic background of the mice is a crucial element in deciding how severe the Fgfr2c mutation is manifested.
On the previous CD1 mouse strain, only a small proportion of XY Fgfr2c knockout gonads were sex-reversed ovaries, yet when we bred the Fgfr2c KO mice onto the C57BL/6J strain (which sensitises for XY sex reversal), we suddenly found that almost all XY Fgfr2c KO gonads were ovaries.
We were also surprised that Fgf9-Fgfr2c signalling was involved in repression of the pro-female Foxl2 pathway. Unlike Wnt4 , ovary development proceeds normally in the absence of Foxl2, suggesting it is not a key player in directing ovarian fate. It therefore seemed likely that Foxl2 did not need to be repressed for testicular development to proceed. However, our work confirms that Fgfr2c signalling is required to inhibit Foxl2.
Our results suggest that human mutations in Fgfr2c, already known to cause skeletal defects such as synostosis (premature fusion of bone joints) are likely also giving rise to 'Disorders of Sex Development' (DSDs), such as 46, XY Gonadal Dysgenesis in XY patients.
In addition, since our work shows Foxl2 repression is required for normal testicular development, existing clinical genetic screens designed to identify causative genes in DSD patients can now be modified to include DNA regulatory regions which repress Foxl2. Mutations in these Foxl2 regulatory sites may potentially explain a subset of XY DSD patients. This is important since only ~30% of XY DSD patients receive a genetic diagnosis, and therefore their clinical management is sub-optimal.
Male reproduction and 'Disorders of Sex Development' (DSDs)
Other points of interest
Importantly, this article was chosen as the feature publication of Novembers' issue of Endocrinology (https://academic.oup.com/endo/pages/issue_158_11).
This entailed a 'News and Views' commentary article on our study (https://www.ncbi.nlm.nih.gov/pubmed/29099957) as well includes a 3 min youtube clip of the first author (Daniel Bird) explaining the work (https://www.youtube.com/watch?v=OQNteR-LNxE)