Microscopy showing the cellular reprogramming uncovered by EMBL scientists. On the left is an ovary of a normal adult female mouse, with a close-up (top left) showing the typical female granulosa cells. When the Foxl2 gene was silenced in these cells (right, top right: close-up), they took on the characteristics of Sertoli cells, the cells normally found in testes of male mice.

Credit: Treier/EMBL

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SYDNEY: Female ovaries spend their entire existence suppressing an innate capacity to become male, according to a new study that overturns existing theories.

The study, published in the journal Cell, could have important implications for understanding sex disorders in humans.

It found that the ovaries of adult female mice could be ‘reprogrammed’ into non-sperm-producing male testes by silencing a single gene, called FOXL2.

Another gene, called SRY and found on the Y chromosome, is responsible for undeveloped foetal gonads becoming male testes, rather than female ovaries. SRY then activates a gene called SOX9, which takes over from there.

Present in both sexes

It has therefore long been considered that if SRY is not present, the organism will develop into a female by default. However, researchers have now discovered that organisms naturally become male, and it is in fact the male development pathway that needs to be actively suppressed. This is the job of FOXL2.

The gene, which is present in both sexes, has been known for some time to play an important role in female development. It is also to be responsible for male sex reversal syndrome in goats.

However, the fact that it is constantly acting in opposition to SOX9 was only discovered when researchers ‘switched off’ the gene in adult female mice.

“Surprised by the results”

“We were surprised by the results,” said Mathias Treier, co-author of the study and molecular biologist at the European Molecular Biology Laboratory in Heidelberg, Germany.

“We expected the mice to stop producing oocytes [eggs], but what happened was much more dramatic: somatic cells which support the developing egg took on the characteristics of the cells which usually support developing sperm,” he said.

Now, Australian researchers have begun to test how the same gene might affect women.

“Alterations in this gene in humans could result in premature ovarian failure and disorders of sex development,” said Andrew Sinclair, a geneticist from the Murdoch Childrens Research Institute in Sydney, in a preview of the paper which was also published in Cell.

Sinclair is leading a new study examining women with premature ovarian failure and sex development disorders, and, given the recent findings, will now examine whether alterations in their FOXL2 gene could be to blame.

Theory overturned

Jenny Graves, a geneticist from the Australian National University in Canberra, says she is “amazed” by the results of the study and thinks scientists may need to re-consider what they have previously thought about the interaction between SRY and FOXL2.

The significance of this study, she said, was the decision to silence the FOXL2 gene in adult females, rather than developing foetuses, as had been done in the past.

“We’ve always known that FOXL2 has something to do with sex, but there has been no clear cut case of sex reversal until now,” she said.

The researchers also discovered that FOXL2 suppresses SOX9 in cooperation with the oestrogen receptor, which could help to explain occasional signs of masculinisation in menopausal women.