LONDON — Two separate genes are responsible for determining male and female sex during mammalian embryonic development, researchers in the U.K. have established.

They have identified a gene on the X chromosome which ensures female development — potentially making it the equivalent of the Sry gene on the Y chromosome, which already is known to be needed for development as a male.

The discovery suggests that, rather than development as a female happening by default in the absence of a Y chromosome, it is controlled by the newly identified gene on the X chromosome, called Dax1. Both Dax1 and Sry are thought to encode transcription factors, proteins that turn on and off the expression of two hierarchies of genes controlling the development of female and male sex, respectively.

Robin Lovell-Badge, head of the division of developmental genetics at the Medical Research Council's National Institute for Medical Research, in London, told BioWorld International, "In normal female development, there is no Sry gene present, so you might think, what is the point of having Dax1?

"We think its role is to make certain that the secondary male genes are turned off — an insurance policy, if you like — to ensure that you do not get any male development in an individual who should be female."

Lovell-Badge, together with colleagues at the National Institute for Medical Research, and at the Universidad Autonoma del Estado de Morelos, in Morelos, Mexico, and the Universita di Pavia, in Pavia, Italy, reported their results in a paper in Nature, Feb. 19, 1998, titled "Dax1 antagonizes Sry action in mammalian sex determination".

The Sry gene is known to be the only gene on the Y chromosome that is required for male development. Mutations in it lead to the development of XY females; and if Sry is added to female mouse embryos as a transgene, some will develop as males rather than as females.

Oddly, however, some XY humans develop as females even though they have an apparently normal Sry gene. In some cases, these individuals have duplicated areas of the X chromosome. XY individuals who have lost the duplicated region also have been described — and they develop normally as males.

Lovell-Badge explained, "These observations were the starting point for our work described in the Nature paper. The XY individuals who have this area of the X chromosome deleted but who develop normally as males demonstrate that there is no gene in this region leading to male development — but the fact that when this area is duplicated it seems to promote female development suggests that there may be a gene in here that is required for female development."

Male, Female Genes Antagonistic

Giovanna Camerino, of the Universita di Pavia, who is one of Lovell-Badge's co-authors, searched with colleagues within the duplicated region for a candidate gene, and identified Dax1. Lovell-Badge and his team then set out to test whether Dax1 was indeed responsible for the human syndrome of XY females.

They decided to do this by duplicating the mouse Dax1 gene to see whether this resulted in XY female mice.

Lovell-Badge told BioWorld International, "Essentially this worked, although it was not as simple as we had hoped it would be. We found that the more expression of Dax1 you had, the more likely you were to get female development, but that this was encouraged by having weaker alleles of Sry present." The team found that increasing expression of Dax1 and decreasing Sry led to female development, while decreasing Dax1 and increasing the strength of Sry led to male development.

The two genes have an antagonistic effect, said Lovell-Badge. "We think that in normal male development in a normal XY individual, you may have a competition between Dax1 and Sry, but Sry always wins. All our evidence points to both Sry and Dax1 acting on the same critical target genes. Sry is trying to turn the secondary male-determining genes on and make sure that they stay on, while Dax1 tries to make sure they stay turned off."

The team's next goal is to try to understand the hierarchy of genes on which Sry and Dax1 operate. Lovell-Badge concluded, "Through this work and that of others, we are gradually beginning to build up a picture of early events in sex determination and how these act on subsequent events in differentiation of the testes or ovaries. The sex of the rest of the embryo is dependent on the hormonal output of the gonads, particularly on testosterone in the male. So one important connection to be made is how these primary sex-determining genes eventually have an effect on the steroid-producing cells."

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