Knocking out a single gene transforms gonads in mice.
Inside every ovary lurks a testicle just waiting to develop. So says a study in mice that further overturns traditional views of sexual development — and reveals that females must constantly suppress their masculine side.
Mathias Treier, a geneticist at the European Molecular Biology Laboratory in Heidelberg, Germany, and his colleagues deleted a gene called FOXL2 in sexually mature mouse ovaries. When they examined the ovaries three weeks later, they had switched sex and started pumping out the hormone testosterone.
"The major finding is that females must actively suppress the male pathway inside the ovary," Treier says. "Here is a gene that is not located on the sex chromosome that makes you stay female."
In many mammals, sex is determined during the early development of the fetus by the activity of a gene called SRY located on the Y sex chromosome, carried only by males. That gene triggers a second gene, called SOX9, which induces testes development.
But Treier's team have found that FOXL2 is a key 'power broker', acting in conjunction with the cell's oestrogen receptor in order to inhibit SOX9 in adult females and preventing the ovaries from producing testosterone. The study is published this week in Cell1.
This study is not the first to transform adult ovaries into testes. In work published in 1999 in Science, John Couse, then at the US National Institute of Environmental Health Sciences in North Carolina, and his colleagues knocked out both types of oestrogen receptor in mice and found that the gonads showed signs of changing sex, but they did not produce testosterone2. High levels of oestrogen can also trigger sex changes in a number of animals, including marsupial mammals.
But the finding that ovaries must actually strive to keep their identity makes this "a very exciting piece of work", says Richard Anderson, a reproductive endocrinologist at the Queen's Medical Research Institute at the University of Edinburgh, UK, who has studied FOXL2. "What they are proposing is that the ovary is not a fixed structure but must maintain its 'ovary-ness'," he says.
Treier had expected to achieve sex reversal in the mice by knocking out FOXL2 early in sexual development, rather than having to wait until the mice were mature. He was puzzled to find that knocking out the gene in immature mice stopped the ovaries from developing properly and led to their degeneration. He says that it has taken his group ten years to understand the gene's true role in sex determination.
Treier believes that FOXL2 could be one of the oldest sex-determining genes in vertebrates. For example, it is known that female goats that are missing the section of chromosome containing FOXL2 develop as males. Regulation of the gene may also enable female fish to change sex after sexual development, and FOXL2 could underlie the masculinization seen in some menopausal women, Treier says.
Because the ovarian cells that give rise to eggs were not modified by the gene deletion, Treier's transsexual mice could not make sperm. The next step, he says, is to add sperm stem cells to these modified ovaries to see if they can produce sperm. "It's outlandish, and the chance that it will work is very small," he says. "But you never know."
Uhlenhaut, N. H. et al. Cell 139, 1130-1142 (2009).
Couse, J. F. et al. Science 286, 2328-2331 (1999).