Secret To Testis Development Lies In Gene Interaction

Main Category: Genetics
Article Date: 08 May 2008 - 4:00 PDT

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The relationship between two genes that work in synergy to form the testicles has been uncovered by scientists working at the MRC National Institute for Medical Research. The discovery sheds light on how just a single gene difference between XX (female) and XY (male) embryos is amplified, eventually generating the dramatic differences in anatomy, physiology and behaviour between the sexes. The study results are published online in Nature.

It is known that the sex of an embryo depends on the presence or absence of a gene called Sry on the Y chromosome. This gene sparks the development of cells into those that will eventually support creation of sperm. When Sry is not present, these same cells differentiate into those typical of ovary tissue with the ability to support egg development.

The second gene, Sox9, is present in both male and female embryos because it is not carried on either the X or Y sex chromosomes. Previous studies have shown that even in the absence of Sry, if Sox9 is expressed abnormally in an XX (female) embryo, testes can develop. What was not understood until now is how Sry affects Sox9.

By studying genetic events in mice, the team discovered that SRY, the protein encoded by Sry, binds to a specific part of the Sox9 gene that enhances its activity. It does this along with another regulatory protein called SF1, which is present in both XX and XY cells, but is unable to trigger male development by itself. This creates a self-reinforcing pathway - by interacting with SF1, the SRY protein boosts the activity of the Sox9 gene. SRY is present for a brief period, but by the time it fades away there is sufficient SOX9 protein present to join forces with SF1 and bind to its own enhancer. In this way, SOX9 helps to maintain itself at a high level. SOX9 can then promote the activity of other genes responsible for cells developing into testes.

Co-author of the study Dr Robin Lovell-Badge of the MRC National Institute for Medical Research explained the importance of the relationship between Sry and Sox9:

"This small regulatory region we have found is responsible for integrating not only all the positive signals that initiate, up-regulate and maintain Sox9 expression in the testis, but also the repressive signals that shut off the gene during ovary development. Learning more about it will help to define the nature of the genes that guide development of cells into those characteristic of either testis or ovaries.''

''The role of the Sox9 gene appears to be the same in all vertebrates, but Sry is only present in mammals. Studying how and where the DNA sequence of the Sox9 enhancer varies from one species to the next may reveal much about the rapid evolution of sex determining mechanisms. It should also provide insights into how these mechanisms go wrong in some people," he concludes.

Original research paper: Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer is published online in Nature.

Medical Research Council