Sry isn't the key to maleness after all!

` I thought this was fascinating: According to Nature News, the gene Sry isn't the only way that an embryo can start development into a male - even though XX males typically carry an Sry (normally found on the Y chromosome). There are exceptions:

The team studied a family in which four brothers were each XX. None carried the 'male' SRY gene. Instead, the team reports in Nature Genetics², they each have a mutation in a gene called RSPO1.

It seems that sex is determined in humans by a cascade of genes. At a crucial junction in this process lies a gene called SOX9, which in males is switched on by SRY, causing testis development. In females, the researchers now suggest, SOX9 might be typically switched off by RSPO1, which, via other genes in the cascade, leads to the development of ovaries. In the brothers, it seems the mutated RSPO1 gene could not fulfil its switching-off role, leaving SOX9 on and leading to male development.

This theory fits with animal studies: mice with two X chromosomes that have their SOX9 expression turned back on form testes.³

` So, the determination of which sex an embryo becomes is now a bit clearer and more complex....

"What is really important is that suppression of male and induction of female development is an active process," says Andreas Schedl of INSERM, the French National Institute of Health and Medical Research in Nice, who is a co-author on the paper. "RSPO1 clearly plays a key role in this process." The identification of this gene, he says, may be as important to the field as the identification of SRY.

RSPO1 encodes for a protein that is something of a multi-tasker — as well as being a key player in the sex-determining pathway, it also causes all the males in this family to suffer from a skin-thickening condition, and predisposes them to skin cancer. Understanding how it does this might help researchers to confirm its exact role in sex determination.

The next step, say the researchers, is to find out what happens when the RSOP1 gene is knocked out of mice.

` Indeed! That should answer a few questions....