Genetic switch that turns mice ovaries into testes

Scientists have found that a single gene maintains femininity in adult mice, and that when it is switched off they develop male features. The findings may help understand sex disorders in children or premature menopause in women.

The gene, called FOXL2, was known to be important for the growth of ovaries during development and for their maintenance throughout life. It has a converse expression profile to SOX9, another gene that is active in males. Both of these genes lie on non-sex chromosome that are shared by both males and females. In almost all mammals, females have two X chromosomes and males have one X and one Y chromosome. The genes inherited on these chromosomes determine their gender traits. A transcription factor called SRY that is on the Y chromosome is responsible for triggering gonads to turn into testes during fetal development, and then switching on SOX9. The theory was previously that if SRY was not present, the gonads become ovaries by default.

This new work shows that FOXL2 is actively required to keep SOX9 turned off in adult ovaries. The scientists switched off FOXL2 in adult mice and found that the male gene SOX9 was immediately switched on. This sent chemical signals that turned the female ovary cells into testosterone-producing cells that were like the cells found in testes. The levels of testosterone produced by these previously female mice were the same as the levels produced by normal male mice. The physical effects of this switch are difficult to assess in mice, however, as they have less obvious physical gender specific traits than humans.

'No one would have betted on this,' said Mathias Treier of the European Molecular Biology Laboratory, Germany, who led one of the teams carrying out the study. 'That's why the finding is so spectacular', he added.

FOXL2 was also found to work in cooperation with the oestrogen receptor to suppress SOX9, and without FOXL2 the oestrogen receptor cannot function. Treier thinks that this may explain why some post-menopausal women exhibit signs of masculinisation.

The scientists anticipate that, in humans, the effect of silencing the FOXL2 gene with gene therapy could be similar to that of gender reassignment therapy when a testosterone tablet is given to women, which results in them losing their breasts, growing facial hair and their voices deepening. They also speculate that the opposite effect could be seen in males if the SOX9 gene was suppressed.

The work challenges the age-old dogma of sex determination that says that gender is fixed from birth. Dr Robin Lovell-Badge, from the National Institute for Medical Research, London, was a co-author of the study. He says: 'we take it for granted that we maintain the sex we are born with, including whether we have testes or ovaries. But this work shows that the activity of a single gene, FOXL2, is all that prevents adult ovary cells turning into cells found in testes. If it is possible to make these changes in adult humans, it may eventually remove the need for surgery in gender-reassignment treatment'.