The Battle of the Sexes

Describe yourself to me in five words. I’m willing to bet that (once I’d eliminated all the rude and ‘witty’ responses) I could guess most of the things you would deem important enough to tell me. Name, age, occupation and sex are factors that most people use to define themselves. Arguably the most important of these is sex.

The two sexes are more closely linked than we thought

The two sexes are more closely linked than we thought

Gender in mammals is defined at the moment of conception, based on which chromosomes you inherit from your parents. Two X chromosomes result in a female baby, one X and one Y chromosome results in a male. This is because XX ‘female’ embryos develop ovaries, which release hormones such as oestrogen, while XY ‘male’ embryos develop testosterone-producing testicles.

Your gender affects your physiology and sense of identity, and so affects how you think about and respond to many situations. It’s likely, then, that you think of your sex as pretty immutable. But think again. A single gene is the only thing standing between you and an involuntary sex change.

The extraordinary fragility of sex in mammals was first highlighted in by studies on a gene called Foxl2, which is turned on in XX, but not XY embryos. Foxl2 is essential for normal development of the ovaries in XX embryos. Researchers deleted Foxl2 in adult XX mice, after the ovaries were fully formed. They found that, over a four week period, the ovaries of the genetically engineered mice became testicles. Almost every cell type within the ovary had become its male counterpart. So, for example, the cells responsible for making female hormones such as oestrogen transformed into the equivalent male cell type, and began to produce testosterone.

Nor is the process one-way. A group studying a gene called Dmrt1 recently performed the complementary experiment. Dmrt1 is essential for growth of the testicles in XY embryos, and is turned off in XX embryos. Researchers deleted Dmrt1 in XY mice. Voila! Ovaries appeared where the testicles once were.

These experiments demonstrate a remarkable phenomenon; the cells of our sex organs (the ovaries and testicles) are constantly battling to maintain their sexual identity. These organs must keep a ‘gender-maintaining’ gene, either Foxl2 or Dmrt1, turned on at all times. One slip-up is enough to begin a slide towards sex change.

That an ovary can become a testicle or vice versa is an astonishing transformation; one functioning organ has the capacity to become quite another. The key to the ease with which the sex organs interchange lies in the fact that they both started life as the same structures, called the gonads. The gonads form in both XX and XY embryos, and initially have neither male nor female characteristics. As XY embryos grow, a single gene on the Y chromosome, called Sry, is turned on, and instructs the gonads to develop into testicles. XX embryos lack a Y chromosome, so they do not receive this signal; their gonads develop into ovaries.  The upshot of this is that many of the different cell types in the ovary and testicles have similar origins, so each cell type can easily flip-flop between male and female characteristics.

The gonad (on the left) can become a testis (top) or an ovary (bottom). The important bit is the pics on the right, where you can see that the testis and ovary have the same cell types

The gonad (on the left) can become a testis (top) or an ovary (bottom). The important bit is the pics on the right, where you can see that the testis and ovary have the same cell types

Although it seems quite fantastical that mice can change sex at the flip of a switch, amphibians and other lower vertebrates have long been performing such feats. Species of frog and toad can change sex under environmental pressure, for example if one sex is under-represented in the population. In fact, as both Foxl2 and Dmrt1 are found throughout vertebrate evolution, it is possible that gender is controlled by similar mechanisms in many species.

This raises the possibility that manipulation of these ‘gender-maintaining’ genes could be used in sex change patients. In theory, causing a change in the physiology of the patient’s sex organs would bring about a more natural and less invasive beginning to the sex change process.  But it remains to be seen whether loss of a gender-maintaining gene would also alter your sense of identity. Would a change in psychology accompany a change in physiology?  It is true that sex change in amphibians is associated with behavioural changes. In mammals, however, differences in how the brain is wired in males and females is dependent not only on what hormones are available, but also on many genes found on the X and Y chromosomes. Our sense of self as male or female is not dependent purely on our anatomy.

These studies highlight how gender, normally regarded as sturdy and irreversible, actually balances on the edge of a knife. So, the next time you tick the male or female box on a questionnaire, or write a description of yourself for a job application, spare a thought for Foxl2 and Dmrt1. Within your body there rages an ongoing battle for sexual dominance.

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4 thoughts on “The Battle of the Sexes

  1. This is fascinating Jen, thanks! Any cancer risk from taking away the ‘gender maintaining gene’? Does the opposite sex one automatically activate itself?xx

    • Thanks for your comment Alixji! Great questions.

      It seems that if you delete Dmrt1 in the male mouse embryo, (rather than in the adult, which is what they did in the experiments I’ve written about) the mice develop testicular tumours – see here for the paper, although I think it’s paywalled. This isn’t due to a sex change, but because of problems with the cell cycle in the germ cells (which would normally become sperm). There is some evidence to suggest that Dmrt1 mutation is linked to testicular cancer in humans, but nothing concrete yet – here, again, paywall. It’s an attractive theory because in these cancers the testes often have feminine-like characteristics – they don’t descend properly, or they’re small, for example. So although it’s possible that taking away Dmrt1 in adults would cause cancer, no one knows for sure.

      As for Foxl2 – no one really knows. We do know that its genetic sequence is altered in a rare type of ovarian tumour, called granulosa cell tumour (see here). People don’t know what this alteration does – it doesn’t stop Foxl2 from working, like in the mouse experiments. It might be that it changes how FOXL2 protein interacts with other proteins. But there’s no reason to suspect that taking it away would cause cancer.

      Finally, yes, the opposite gender-gene automatically activates if its opposite is removed. The scientists who performed the Dmrt1 experiments think that this is what is known as a ‘direct’ interaction, meaning that Dmrt1 protein sits on the DNA close to Foxl2 to stop it from turning on, and vice versa. If the protein is no longer made, there’s nothing to stop the other gene from turning on.

      Hope that helps, please let me know if you have any more questions, or if I’ve been clear as mud!

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