Sex change. A normal mouse ovary (left), and one lacking Foxl2.

© M. Treier/EMBL

A Delicate Balance of Sexual Identity

The difference between male and female is smaller than one might think--at least on a cellular level. Researchers have found that they can change ovary cells into testicular cells in mice by turning off a single gene. The discovery provides new insights into the evolution of sex differences, and it may help doctors better understand sexual identity disorders and why some women go through early menopause.

Scientists knew that the gene responsible for the fate switch, called Foxl2, was important to ovarian cells. But experiments with the gene had led to confusing results, says developmental biologist Mathias Treier of the European Molecular Biology Laboratory in Heidelberg, Germany. Female mice lacking the gene developed perfectly normal ovaries. After birth, however, the animals' ovaries started to deteriorate. But it was not clear what was going wrong.

To learn more, Treier and his colleagues genetically engineered a mouse in which they could selectively turn off the Foxl2 gene in adult ovaries. With the gene inactive, a dramatic change took place in the female mice. Within 3 weeks, their ovaries were full of tubelike structures usually found in testicle tissue. Upon closer inspection, the researchers found that the ovarian cells had become cellular cross-dressers, displaying all the characteristics of several types of testicle cells, some of which produced levels of testosterone typical of an adult male. (There were no sperm present, however.)

Foxl2, it seems, is part of a larger genetic pathway that controls the identity of cells in the ovaries and testis. The researchers found that the protein made by the gene suppresses the activity of another gene called Sox9, which prompts the development of testicular cells. When Foxl2 is turned off, Sox9 is free to take over--and turn the ovary cells into testis cells, the team reports in today's issue of Cell. The work shows that the adult gonad has "remarkable plasticity," says developmental biologist Andrew Sinclair of the University of Melbourne in Australia, who was not involved in the research.

During embryonic development, there are several mutually reinforcing gene pathways that keep an organism either male or female. Indeed, says developmental biologist Robin Lovell-Badge of the MRC National Institute for Medical Research in London, who worked with Treier on the study, there are so many overlapping mechanisms that keep the sexes developing in their own direction, "you would have thought that by the time you get to the adult, everything would be so hard-wired you couldn't change it." But the new work shows that by adulthood, the backup reinforcements are no longer active, so that a change in the levels of a single protein is enough to trigger a dramatic switch.

Mammals, fish, and birds have all evolved different systems of sex chromosomes that determine whether an organism is male or female, but the Foxl2 and Sox9 genes are conserved in all vertebrates. So Treier says that the yin-yang balance between the two is probably active in maintaining sex in a wide variety of animals. Several species of fish are known to be able to change their gender in adulthood, and Sinclair says the new results may explain how that happens. The pathway is also interesting for researchers studying early ovarian failure, which causes some women to undergo early menopause. And it may also help explain why some children develop sexual characteristics that don't match their chromosomal gender.

Lovell-Badge says he and his colleagues are now looking for whether a similar genetic trick can change male cells into female cells. In any case, he says, the findings disprove the idea, long held by developmental biologists, that female characteristics are a default setting that is overwritten by male genes--a bit of gender equality at the cellular level.