Sex determination: Exploring XX males 16/01/07. By the Wellcome Trust A newly discovered growth factor might play a vital role in sex determination.

Carrying an X and a Y chromosome does not necessarily make you male. Maleness is driven by the SRY gene on the Y chromosome, so if SRY is mutated, development proceeds along the default, female pathway – a condition termed XY sex reversal. Rarely, XX (female to male) sex reversal can occur, usually due to translocation of SRY to another chromosome.

A new player in the balance between male and female development has been identified by an Italian team studying XX males. These males did not have the SRY gene, but did have mutations in the RSPO1 gene, encoding a growth factor called R-spondin1.

Why should these mutations cause maleness? Normally, SRY activates the Sox9 gene, which turns on the testis development pathway and is stabilised in the gonad by Fgf9. Conversely, the gonad can be pushed towards ovary development by the Wnt and b-catenin pathways, which antagonise Fgf9. The new research suggests that R-spondin1 works with Wnt and b-catenin genes in repressing the male pathway, so if RSPO1 is mutated, the balance will tilt towards Fgf9 and Sox9, and testes will develop.

References

Parma P et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat Genet 2006;38(11):1304–9. Abstract