One gene keeps Mickey from turning into Minnie
On the surface, it looks as if our identity as male or female is determined in the womb. The decision seems final – a genetic switch flicks towards either setting, and locks into place for the rest of our lives.
This tidy image is wrong. Two recent studies in mice have shown that the switch isn’t locked – it’s held under constant tension by two rival genes – DMRT1 and FOXL2. It’s a tug-of-war fought over sexual fate, which goes on throughout our lives. Take away either contestant, and its adversary pulls the switch to the opposite setting. Ovaries can transform into testes and vice versa, even in adults.
By default, mammal embryos develop as females. A structure called the gonadal ridge eventually gives rise to the ovaries. It’s the presence of a gene called SRY that diverts the embryo down a male route. SRY sits on the Y chromosome and sets of a chain of activated genes that transform the gonadal ridge into testes instead. With SRY, you get a male; without it, a female.
But two years ago, Henriette Uhlenhaut from the European Molecular Biology Laboratory showed that this pivotal moment is not a permanent one. She found that a gene called FOXL2 keeps maleness at bay, long after the gonadal ridge has transformed into ovaries. By deleting it, Uhlenhaut turned the ovaries of female mice into testes. They didn’t produce any sperm, but they cells looked like testicular cells, they had the same portfolio of active genes, and they produced testosterone.
Now, Clinton Matson from the University of Minnesota has found that a gene called DMRT1 acts as FOXL2’s mirror counterpart, suppressing femaleness in male mice.
In fact, DMRT1 and FOXL2 repress each other. Neither can rise to power while the other is strong – this is why sex appears to be so stable. Matson dispelled this illusion by removing DMRT1 in both embryonic and adult mice.
When he bred mice that lacked DMRT1, males would grow up as females. Their gonadal ridges begin to transform into testes, but they are eventually waylaid by the feminising FOXL2. Even when Matson deleted DMRT1 in adult mice, FOXL2 was released and started switching on ovarian genes. Within a month, the testicular cells had been reprogrammed into ovarian ones. These cells produced oestrogen, and flooded the rodents’ bloodstreams with this hormone; meanwhile, their testosterone levels fell.
You can see this clearly in the photo above. The main image is a slice through the organ that would normally be the testes, in a male mouse that lacks DMRT1. The inset is a similar slice through the ovaries of a normal female mouse. Both have two types of cells found in the ovary – granulosa cells (round and magenta) and theca cells (long and magenta, surrounded by green). The magenta colour reveals the presence of FOXL2.
Mathias Treier, who led Uhlenhaut’s FOXL2 study, welcomes the new study. “When we tried to publish our paper that ovaries can be reprogrammed to testis, we were fighting an uphill battle against an old dogma that mammalian sex determination is final,” he says. “It is gratifying for us to see that the reverse is also possible.”
DMRT1 and FOXL2 are not the only genes involved in setting and maintaining our male or female identities. Both of them activate and repress a swarm of other masculinising and feminising genes. But it’s clear from Uhlenhaut and Matson’s experiments that this duo plays a central role in the genetic battle of the sexes.
Of course, these studies were done in mice, but there’s every reason to think that the same antagonism rages on in humans. For a start, both DMRT1 and FOXL2 have very similar counterparts across a wide range of species, and they’re all involved in determining sex. Chickens and medaka fish with silenced versions of DMRT1 will grow up as females even if they are genetically male.
Both genes are also involved in human genetic disorders. People who inherit faulty copies of FOXL2 can develop a rare disease called BPES, which often leads to infertility because the ovaries don’t develop properly. On the flipside, people who are born without any copies of DMRT1 can develop Swyer syndrome. Even if they have a Y chromosome, their testes never develop properly and they are born as normal girls, complete with uterus and vagina. But they don’t have proper ovaries either and as such, they don’t go through puberty – that’s what usually gives away their missing genes.
Understanding how sex is determined could help us better understand these disorders and develop treatments for them. “Both findings will have huge implications for reproductive biology. We may have to look in a new way at reproductive disorders,” says Treier. It might even change how doctors carry out gender reassignment therapies, paving the way for genetic approaches rather than multiple painful surgeries.
Reference: Matson, Murphy, Sarver, Griswold, Bardwell & Zarkower. 2011. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature http://dx.doi.org/10.1038/nature10239
More on sex determination:
- One gene stops ovaries from turning into testes
- Sex runs hot and cold – why does temperature control the gender of Jacky dragons?
- Every cell in a chicken has its own male or female identity
- How prehistoric sea monsters sorted males from females
- Skinks set their sex in three ways – genes, temperature and egg size
- When the heat is on, male dragons become females
You can see this clearly in the photo above. The main image is a slice through the organ that would normally be the testes, in a male mouse that lacks DMRT1. The inset is a similar slice through the ovaries of a normal female mouse. Both have two types of cells found in the ovary – granulosa cells (round and magenta) and theca cells (long and magenta, surrounded by green). The magenta colour reveals the presence of FOXL2.
Go Further
Animals
- This ‘saber-toothed’ salmon wasn’t quite what we thoughtThis ‘saber-toothed’ salmon wasn’t quite what we thought
- Why this rhino-zebra friendship makes perfect senseWhy this rhino-zebra friendship makes perfect sense
- When did bioluminescence evolve? It’s older than we thought.When did bioluminescence evolve? It’s older than we thought.
- Soy, skim … spider. Are any of these technically milk?Soy, skim … spider. Are any of these technically milk?
- This pristine piece of the Amazon shows nature’s resilienceThis pristine piece of the Amazon shows nature’s resilience
Environment
- This pristine piece of the Amazon shows nature’s resilienceThis pristine piece of the Amazon shows nature’s resilience
- Listen to 30 years of climate change transformed into haunting musicListen to 30 years of climate change transformed into haunting music
- This ancient society tried to stop El Niño—with child sacrificeThis ancient society tried to stop El Niño—with child sacrifice
- U.S. plans to clean its drinking water. What does that mean?U.S. plans to clean its drinking water. What does that mean?
History & Culture
- Meet the original members of the tortured poets departmentMeet the original members of the tortured poets department
- Séances at the White House? Why these first ladies turned to the occultSéances at the White House? Why these first ladies turned to the occult
- Gambling is everywhere now. When is that a problem?Gambling is everywhere now. When is that a problem?
- Beauty is pain—at least it was in 17th-century SpainBeauty is pain—at least it was in 17th-century Spain
- The real spies who inspired ‘The Ministry of Ungentlemanly Warfare’The real spies who inspired ‘The Ministry of Ungentlemanly Warfare’
Science
- Here's how astronomers found one of the rarest phenomenons in spaceHere's how astronomers found one of the rarest phenomenons in space
- Not an extrovert or introvert? There’s a word for that.Not an extrovert or introvert? There’s a word for that.
- NASA has a plan to clean up space junk—but is going green enough?NASA has a plan to clean up space junk—but is going green enough?
- Soy, skim … spider. Are any of these technically milk?Soy, skim … spider. Are any of these technically milk?
- Can aspirin help protect against colorectal cancers?Can aspirin help protect against colorectal cancers?
Travel
- What it's like to hike the Camino del Mayab in MexicoWhat it's like to hike the Camino del Mayab in Mexico
- Is this small English town Yorkshire's culinary capital?Is this small English town Yorkshire's culinary capital?
- This chef is taking Indian cuisine in a bold new directionThis chef is taking Indian cuisine in a bold new direction
- Follow in the footsteps of Robin Hood in Sherwood ForestFollow in the footsteps of Robin Hood in Sherwood Forest