MRC National Institute for Medical Research, London
Science for Health
Secret to testis development lies in gene interaction
07 May 2008
Sex determination in mammals depends on the presence or absence of the Y chromosome gene Sry. The gene product, SRY, which contains an HMG box DNA binding domain, acts very transiently to trigger a specific population of cells present in the early gonad to differentiate into Sertoli cells. These are somatic cells characteristic of testes that support and instruct the germ cells to make sperm. In the absence of SRY the same cells give rise instead to follicle cells that are typical of ovaries and function to support egg development. If Sertoli cells are present they instruct other cell types in the early gonad to follow a male pathway, and to secrete factors such as testosterone that are responsible for masculinisation of the rest of the embryo.
Despite being identified in 1990, the molecular mechanism by which SRY acts was unknown. By studying genetic events in mice, Ryohei Sekido and Robin Lovell-Badge (pictured right), of NIMR's Division of Stem Cell Biology and Developmental Genetics, have now shown that SRY acts together with another transcription factor, steroidogenic factor 1 (SF1), which is present from the very earliest stages of gonadal development in both sexes, to up-regulate the expression of Sox9. The latter is a gene related to Sry, and also known to be important for Sertoli cell differentiation, but which is located on an autosome and therefore found in males and females. The proteins SRY and SF1 are shown to bind and activate a specific regulatory region in the DNA at some distance from the region of Sox9 that encodes the SOX9 protein, but once SOX9 levels reach a critical threshold, several positive feedback loops maintain its own expression after that of SRY has ceased. As also shown in the paper, one such regulatory loop involves SOX9 acting on its own enhancer, again in conjunction with SF1. A brief burst of SRY activity is therefore sufficient to tip the balance of gene expression in the early gonad in favour of male development.
In this way, one tiny difference between XX and XY embryos is amplified and extended, eventually resulting in almost all the dramatic differences between the sexes in terms of anatomy, physiology and behaviour.
Co-author of the study Dr Robin Lovell-Badge explained the importance of the relationship between Sry and Sox9:
Some might think that Sry conforms to one particular male stereotype. It is asleep during early development, even when the gonads first begin to form. It then wakes up for a few hours, just long enough to give out an order, instructing Sox9 to do all the hard work, and it even has to rely on another gene, Sf1, to help it do this. Sry then goes back to sleep, its job done. It certainly does not conform to another stereotype - that of the master regulator barking out orders to many genes and exerting control throughout life. Indeed, the latter role is the one played by Sox9, once it is given the green light by Sry and allowed to take charge.
We think 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 therefore help to define the nature of the genes that guide development of cells into those characteristic of either testis or ovaries. Moreover, as the role of Sox9 appears to be conserved in all vertebrates, yet Sry is present only 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.
Original article
The research findings are published in full in:
Ryohei Sekido & Robin Lovell-Badge, (2008)
Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer
Nature, epub ahead of print. Abstract
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