/ Maggie Koerth-Baker / 2 pm Thu, Nov 17 2011
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  • Forget love, biological sex is a battlefield

    Forget love, biological sex is a battlefield

    Gender isn’t a simple thing. A person can be male, female, both, neither, and more—and that identity doesn’t have to have anything to do with the particular genital plumbing they were born with.

    But the plumbing itself—the biological sex, rather than gender or socio-cultural sex—is also a lot more complicated (and interesting) than we often give it credit for. Don’t believe me? Then check out “DMRT1 prevents female reprogramming in the postnatal mammalian testis,” a research letter published in September in the journal Nature.

    That title is full of typical peer-reviewed paper jargon, but let me break it down for you: There’s a genetic factor, present in male mammals, that is vital to making sure those mammals develop male sex characteristics. But it’s not only important during embryonic development. Oh, no. Turns out, this factor must be active in order for a male’s gonads to stay 100% male. Turn it off, even in an adult male, and the cells in his testes will start to take on more feminine characteristics.

    The genetic factor is called DMRT1, and it is not the only thing responsible for maintaining a mammal’s biological sex throughout life. There’s another factor, called FoxL2, that does the same job in females. Scientists already knew about the lifelong necessity of FoxL2. This new research, performed by a team led by Drs. David Zarkower and Vivian Bardwell of the University of Minnesota, confirmed that DMRT1 is FoxL2’s male counterpart.

    It all begins in utero. Mammals—both the mice used in this study, and larger creatures like us—start out effectively sexless, with gonadal organs that aren’t yet either ovaries or testicles. The chromosomes the embryo has determine how the gonads develop, and the hormones produced by the gonads determine a lot of other physical sex characteristics. If the embryo is XY, the gonads will develop into testicles. If it’s XX, the gonads will become ovaries. I’m simplifying a lot here, but this will give you the basic jist.*

    Both DMRT1 and FoxL2 are transcription factors, proteins that control how genetic information gets copied and expressed. They both exist in gonad cells, but the presence or absence of a Y chromosome determines which factor gets to take charge, and which genetic information is put to use. With a Y chromosome, DMRT1 is activated, and it turns undifferentiated gonadal cells into sperm-nurturing Sertoli cells. Without a Y chromosome, FoxL2 takes over, and those same undifferentiated gonadal cells become granulosa cells, which play several important roles in the ovaries. These transcription factors aren’t the only things governing the expression of sex characteristics, but they are important.

    Zarkower and Bardwell’s team compared normal male mice to mutant males that were born lacking a DMRT1 transcription factor. On the surface, the mutant males looked physically male. They had testicles and a penis. But the cells that made up their testicles weren’t normal. By 28 days after birth, most of the testicular cells were expressing FoxL2. The mice looked male on the outside, but inside their gonadal cells were more like those of a female.

    Next, the team tried deleting the DMRT1 transcription factor in adult male mice that had been born normal. Over time, these mice also began to show cellular changes toward FoxL2 expression and cells that behaved more like female granulosa cells than male Sertoli cells. Previous research by other scientists demonstrated that the same basic thing is true for females and FoxL2, Dr. Zarkower told me. Just reversed.

    Turns out, biological sex determination in mice is kind of an ongoing battle. It doesn’t end during fetal development. It doesn’t even end at birth.

    What’s that mean for humans? This part isn’t really clear yet. Naturally-occuring DMRT1 deletions are rare, but they do happen. They can end in a range of effects. Some genetic males born without DMRT1 have small or underdeveloped testes. Others are born with indeterminate physical sex. About 30% of the time, Zarkower said, a natural DMRT1 deletion leads to an XY female—someone who looks physically female on the outside, but who has male genes and nonfunctional gonads instead of either testicles or ovaries. Usually, nobody notices the difference until the person doesn’t experience a normal female puberty.

    Because of that, I wondered whether DMRT1 could be useful for women whose biological sex doesn’t match their female gender identity. If deleting DMRT1 can make an adult male body become more feminized, could doctors someday use that trick to intentionally help transition a biologically male body into a more female one?

    Unfortunately, Zarkower doubts that would work. “This is very new and there’s a lot we don’t know yet, but the external genitalia didn’t change,” he said. “DMRT1 null mice were born physically male, they just didn’t go through puberty properly. In adults, this was basically the same as removing the testes. There would be hormonal changes, but it wouldn’t have an appreciable effect for external genitalia.”

    Beyond that, he said, what happens in mice may or may not translate to humans. For instance, because of the way our genes work, all male mammals have two copies of DMRT1. Mice don’t seem to need both. If you delete one of the copies in a male mouse, the mouse will be essentially normal. Humans, on the other hand, have to have both copies for normal development. More problematic, in humans, mutations of DMRT1 are strongly linked to testicular cancer. “I’d be reluctant to mess around with this in humans,” Zarkower said.

    For now, the main thing we can take away from this discovery is a gentle reminder that our bodies really are weird and wonderful. Even if you’re already used to thinking about gender as a fluid concept, it can be strange to realize how flexible biological sex is, as well. Don’t get too hung up on the idea that “male” and “female” must be set-in-stone categories. Nature certainly doesn’t treat sex that way.

    *Interestingly, other species of animals have very different processes of determining biological sex. For instance, while those gonadal hormones are key for mammals, birds have cells that are individually male or female from the beginning. Because of that, it’s actually possible to have a chicken whose sex is split down the middle of its body—with one side made up of female cells that produce female sexual characteristics and the other side full of male cells that produce male sexual characteristics. When that happens, the bird is called a gyndandromorph. You can read more about that on Ed Yong’s Not Exactly Rocket Science.

    Image: Fig leaves, a Creative Commons Attribution (2.0) image from epredator's photostream

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