December 11, 2009

expert reaction to new research into sex differentiation in mice, as published in Cell

This study identified a single gene responsible for maintaining ovary development during sex differentiation in mice, improving current understanding of how genetic factors influence sexual development.

Prof Richard Anderson, Centre for Reproductive Biology, University of Edinburgh, said:

“This is a very interesting and novel study that causes us to rethink how the differences between males and females are maintained. It sheds significant light on the flexibility of ovarian programming throughout life, and suggests that sex differentiation might be constantly maintained rather than being something that is fixed from birth. Historically it has been believed that in mammals the female is the ‘default’ sex, with male development only occurring in the presence of a Y chromosome and a particular set of genes. However, it has more recently been recognised that a number of ‘femaleness’ genes also exist, and it seems that these genes need to be active throughout life, not just during early development.

“How this important piece of basic laboratory science will translate into the clinical setting is not clear yet. What is clear however is that there are basic mechanisms of sex determination and adult ovarian function that are very incompletely understood at present and which may be important in a range of conditions such as premature menopause.”

Prof Ieuan Hughes, Head of Department of Paediatrics, University of Cambridge, said:

“This is an excellent body of work and adds a bit more to the jigsaw of how testis and ovary development determine the phenotypic sex in mammals.

“It is currently accepted that in mammals, including humans, the presence of XY sex chromosomes initiates formation of the testis in early life and hence male development. In contrast, the presence of XX chromosomes leads to formation of the ovary and female development. A key factor on the Y chromosome called SRY orchestrates the regulation of a panoply of genes, particularly SOX9, which ensures a testis is formed. There are examples of human males that have XX chromosomes, so how do they develop testes without the Y chromosome? In the vast majority, this anomaly is explained by a tiny piece of the Y chromosome which houses the SRY gene being transferred at fertilisation to the X chromosome. But, a small minority of so-called XX males do not have this key SRY factor. So how do they develop testes?

“The present study published in Cell may explain how such sex reversal could occur, at least in the mouse. It has been accepted dogma that the constitutive sex in mammalian development is female. Male development will only occur in the presence of a Y chromosome and the activation of a panel of testis determining genes. Any deviation from that dogma is often explained on the basis of over-expression of genes that act in an anti-testis manner to realise XX sex reversal. But can ovarian and hence female development, be an active process rather than passively constitutive? The mouse ovary has a factor called FOXL2 (Forkhead transcriptional regulator) that is essential to prevent the ovary in adult life from changing to a testis. When the function of the FOXL2 gene is disrupted in mouse follicles, the surrounding cells start producing SRY and SOX9, the very factors that are key to making a testis. Sure enough, in these elegant mouse experiments performed by Uhlenhaut and co-workers, the surrounding cells started producing the male hormone, testosterone, at levels seen in normal testes. These experiments used adult, not fetal or infantile ovaries.

“The findings may have relevance to human disorders such as early menopause where the ovary for some reason fails to continue producing enough of the female hormone, estrogen. It is less likely that these experiments have relevance to the potential treatment of infants and children with disorders of sex development as the ovary is definitely ‘silent’ functionally before puberty. Nevertheless, this study has confirmed that FOXL2 now takes its place amongst the pantheon of sex determining factors and adds a further piece to the jigsaw that encapsulates the ‘Yin and Yang’ of testis versus ovary development.”