National Geographic

One gene stops ovaries from turning into testes

In science, we don’t often get to talk about male repression, but a new discovery gives us just such a chance. It turns out that ovaries can only remain ovaries by constantly suppressing their ability to become male. Silence a single gene, and adult ovaries turn into testes. That adult tissues can be transformed in this way would be surprising enough, but doing so by changing a single gene is truly astonishing.

As embryos, our gonads aren’t specific to either gender. Their default course is a female one, but they can be diverted through the action of a gene called SRY that sits on the Y chromosome. SRY activates another gene called Sox9, which sets off a chain reaction of flicked genetic switches. The result is that premature gonads develop into testes. Without SRY or Sox9, you get ovaries instead.

But Henriette Uhlenhaut from the European Molecular Biology Laboratory has found that this story is woefully incomplete. Maleness isn’t just forced onto developing gonads by the actions of SRY – it’s permanently kept at bay by another gene called FOXL2.

Uhlenhaut developed a strain of genetically engineered mice, whose copies of FOXL2 could be deleted with the drug tamoxifen. When she did this, she found that the females’ ovaries turned into testes within just three weeks. The change was a thorough one; the altered organs were testes right down to the structure of their cells and their portfolio of active genes. They developed testosterone-secreting Leydig cells, which pumped out as much of the hormone as their counterparts in XY mice. They only fell short of actually producing sperm.

Uhlenhaut found that FOXL2 and SOX9 are mutually exclusive – when one is active, the other is silent and vice versa. The two genes are at opposite ends of a tug-of-war, with sex as the prize. FOXL2 sticks to a stretch of DNA called TESCO, which controls the activity of Sox9. By sticking to TESCO, FOXL2 keeps Sox9 turned off in the adult ovary. Without its repressive hand, Sox9 switches on and sets about its gender-bending antics.

FOXL2 also has a partner-in-repression – the oestrogen receptor, a docking molecule for the hormone oestrogen. The two proteins interact with one another and they cooperate to block Sox9.

The same genes may help to explain the frequent acts of gender-swapping among, fish, reptiles and birds (no, Steve Connor, “one of the great dogmas of biology” is not that “gender is fixed from birth”). In these animals, oestrogens often cause males to change sex into females, and falling levels of oestrogen can trigger the reverse transformation. FOXL2 may also be involved.  

The fact that oestrogen helps to maintain the gender of mice is surprising. Unlike other back-boned animals, mammals are thought to be largely insensitive to levels of sex hormones outside of development. However, Uhlenhaut suggests that oestrogen’s role in keeping ovaries and ovaries may explain why women sometimes appear slightly more masculine after the menopause, a time characterised by falling oestrogen levels.

There have been hints from many species that FOXL2 plays an important role in determining sex. People who inherit faulty copies of the gene can develop a rare disease called BPES that often leads to infertility because of failing ovaries. Goats whose FOXL2 isn’t controlled properly develop a condition called polled intersex syndrome (PIS), where they become males despite carrying two X chromosomes. Females that lack the gene altogether fail to develop proper ovaries at all.

Understanding how gender is set and maintained is vital, for it is such a basic and pervasive element of our lives. Uhlenhaut’s work isn’t just of academic interest. It could also help to treat disorders of sexual development. It could also change how gender reassignment therapies are done, paving the way for gene therapies rather than multiple painful surgeries.

Reference: Uhlenhaut, N., Jakob, S., Anlag, K., Eisenberger, T., Sekido, R., Kress, J., Treier, A., Klugmann, C., Klasen, C., & Holter, N. (2009). Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation Cell, 139 (6), 1130-1142 DOI: 10.1016/j.cell.2009.11.021

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There are 28 Comments. Add Yours.

  1. djlactin
    December 16, 2009

    “When she did this, she found that the females’ ovaries turned into testes within just three weeks.”
    Adult females or embryos?

  2. Monimonika
    December 16, 2009

    @1
    I’m assuming adult females since the post is about adult ovaries turning into testes.

  3. Kathy Orlinsky
    December 16, 2009

    It’s also interesting that the Y chromosome appeared on the scene later than the Foxl2 gene, evolutionarily speaking. Was the original default for embryos male, rather than female?

  4. Anodyne
    December 16, 2009

    My mother says that this “proves” that woman came from man, “just like it says in the bible”.
    I’m very unfamiliar with biology in relation to chromosomes and sex development, so I was hoping someone can refute her assessment with actual facts. It’s GREATLY appreciated!!

  5. Captain Skellett
    December 16, 2009

    Well seeing as the default pathway is female (so if an embryo has no y chromosome or only one x chromosome), I would say that suggests females came first. Suppose it depends on how you define male and female, doesn’t it? Egg laying creatures came before sexes were differentiated, so in some sense they were all females. Some animals are still capable of a virgin birth, a process called parthenogenesis.
    Hope this helps you get the upper hand :)

  6. Larry Hanson
    December 16, 2009

    I just found this site. Suddenly the computer given me by my great-nephew is worthehile. hank you!

  7. Katherine
    December 16, 2009

    “are at opposite ends of a tug-of-war, with sex as the prize.”
    This sentence made me laugh… maybe my sense of humour is juvenile but I dunno. Fascinating stuff anyway.

  8. megan
    December 16, 2009

    {{Their default course is a female one, but they can be diverted through the action of a gene called SRY that sits on the Y chromosome. ]]
    As you said and research has shown complex lifeforms are asexual or feminine and only due to a MUTATION and genetic ADDITION for diversity does maleness come about. MEN ARE ABERATIONS OF NATURE for the sole purpose of additional genetics variation vs asexual procreation that has more defect accumulations.
    Nothing is being suuppressed so much as a freak gene is being kept from unorganized expression in a lifeform genetically set to be female. Face it men are freaks and NOT GOD’S image or core will that Eve was based from.
    EVE BEGAT ADAM from HER RIB!

  9. Ed Yong
    December 16, 2009

    Face it men are freaks and NOT GOD’S image or core will that Eve was based from.

    Eve was invisible?

  10. PalMD
    December 16, 2009

    Wow. just…wow.

  11. AllenH
    December 16, 2009

    Eve was invisible to me for a very long time- finally found her. ;) LOL

  12. david
    December 16, 2009

    I remember a phrase parallel to “In science, we” etc. as you began today, phrase made by poor soul in Atlanta, Richard Jewel, who began, “In law enforcement, we” etc..
    As you are a careful and spirited writer, you are perhaps glad to hear some feedback on style on some rare occasions.

  13. Briana
    December 17, 2009

    I don’t know anything about evolutionary development of the sexes, but does this suggest an entirely different system for determining sex in humans before the y chromosome? I don’t think it’s an issue of what came first… this ‘single’ gene seems to have made sex even more complicated. Haw.

  14. Nomen Nescio
    December 17, 2009

    the Y chromosome is just a bunch of genes. nothing saying those genes couldn’t have been passed down as part of other chromosomes back before the odd heritability pattern of our current sex chromosomes arose.
    keep in mind, that whole X/Y, male-line – bound Y-chromosome inheritance scheme is far from universal; other vertebrates even have different schemes altogether, like the avian ZW configuration. the real story is in what the genes do, not necessarily how they’re arranged into chromosomes.

  15. BdN
    December 17, 2009

    MUTATION and genetic ADDITION for diversity does maleness come about. MEN ARE ABERATIONS OF NATURE for the sole purpose of additional genetics variation

    Mmmkay… Then, I guess, every lifeforms that didn’t magically appeared have got to be an aberration of nature…

  16. BdN
    December 17, 2009

    “appear”…

  17. megan
    December 17, 2009

    [[Mmmkay... Then, I guess, every lifeforms that didn't magically appeared have got to be an aberration of nature...]]
    MMmmKay, multi-cellular lifeforms were around procreating/replicating beautifully for billions of years before the development of sexual dimorphism evolved. Welcome late to the party. Sorry your party favors got handed to you after the punch was served. And yes evolution is in essence various aberrations that overtime succeed or don’t in maintaining a lifeform’s existence and success at surviving.

  18. BdN
    December 17, 2009

    MMmmKay, multi-cellular lifeforms were around procreating/replicating beautifully for billions of years before the development of sexual dimorphism evolved.

    And the point being ?

  19. Christina
    December 17, 2009

    It could also change how gender reassignment therapies are done, paving the way for gene therapies rather than multiple painful surgeries.

    While this does hold great potential for transgender people, it wouldn’t eliminate surgeries. Changing gonads would only replace hormone replacement therapy, by producing endogenous sex hormones. It would change how SRS is done, though, as the gonads would no longer have to be removed, but merely altered. ANC if they could figure out how to make the altered gonads produce ova or sperm, it could preserve fertility.

  20. Christina
    December 17, 2009

    And, not ANC. Damn auto fill

  21. Lilian Nattel
    December 18, 2009

    I did wonder about how this might benefit trans people but it’s also just interesting how male and female are more mutable than I might have thought.

  22. m Andrea
    December 19, 2009

    “Understanding how gender is set”
    Just a quibble, but the sentence should read “how biological sex is set”. And yes, I too immediately wondered how this would impact SRS.
    Except you do realize that while mentally healthy people don’t need a vagina in order to wear a dress or hug a baby, the transgendered are under the impression specific genitalia is mandatory.

  23. Rebecca C.
    December 19, 2009

    “Just a quibble, but the sentence should read ‘how biological sex is set’.”
    Not really. “Biological sex” could be defined as determined by which chromosomes you have, not the cellular structure of your gonads or the expression/suppression of hormone-producing genes. I doubt you would refer to folks who were born one sex and adopted a different gender through hormone therapy as having changed their sex. Then again, you think surgically altered trans people are not “mentally healthy,” so I’m not obliged to listen to you.

  24. Sven DiMilo
    December 19, 2009

    Egg laying creatures came before sexes were differentiated, so in some sense they were all females.

    What? No, this is entirely wrong. There is no point in calling a gamete an “egg” unless sexes (of, at least, gametes) are differentiated.

    MMmmKay, multi-cellular lifeforms were around procreating/replicating beautifully for billions of years before the development of sexual dimorphism evolved.

    What? No, multicellularity starts showing up only about one bya, at the outside, and sexual reproduction had been invented well before that.

  25. Sven DiMilo
    December 19, 2009

    Genetic sex determination does not require dimorphic sex chromosomes, and sex determination does not even require dimorphic genes. Crocodilians and most turtles (and some lizards) have temperature sex determination, which may well have been the ancestral from in amniotes.

  26. Muse142
    December 19, 2009

    I must agree with m Andrea above, that your last sentence should speak about sex and not gender. In response to Rebecca, I’ll posit that the structure and function of gonads tend to be thought of as primary sexual characteristics, or that which relate to a person’s sex, while the changes in the body associated with taking hormones are typically secondary sexual characteristics, or that which relate to a person’s gender (but are also related to sex, in that the development of these characteristics are ‘naturally’ caused by the endogenous action of the gonads). Complicated business, but still dissociable I think.
    I must also disagree with m Andrea’s bigoted characterization of people who get sex-reassignment surgery and their relation to stereotypical gender activities, but that much is fairly obvious. Body dysmorphia isn’t something that can be alleviated by hugging a baby or throwing a baseball.

  27. Christina
    December 20, 2009

    I must also disagree with m Andrea’s bigoted characterization of people who get sex-reassignment surgery and their relation to stereotypical gender activities, but that much is fairly obvious. Body dysmorphia isn’t something that can be alleviated by hugging a baby or throwing a baseball.
    Me too. Gender dysphoria isn’t about sex roles. Some trans women wear dresses, some don’t, just like cis (non-trans) women. Transgender people (trans women, trans men, and non-binary trans people) have the same range of behaviors as cis people. If anything, trans people are LESS inclined to believe that behaviors are gender-specific than cis people.
    Also, not all transgender people desire surgery.

  28. Anthony
    December 22, 2009

    So we have a possible species insurance mechanism, if all the males on the planet wiped each other out, would FOXL2 switch off and provide some new ones.

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