The sex reversal technique could be used to help rescue endangered species, say the researchers behind the work.
Scientists have deliberately turned male mouse embryos into females for the first time. A team based in Japan used a CRISPR-based approach to remove the Y chromosome from male cells and create female clones of male mice.
“No one has done this before,” says Monika Ward, a reproductive biologist at the University of Hawaii, who was not involved in the research.
The feat could change the way scientists think about reproduction, says Takashi Ishiuchi, a reproductive biologist at the University of Yamanashi, who co-led the work. The findings were published in a preprint paper shared on bioRxiv earlier this month, which has not yet been through the peer-review process. “There’s a fixed concept in our scientific field that we need both females and males for reproduction,” says Ishiuchi. “I think we could change this concept.”
He and his colleague Shogo Matoba of the Riken BioResource Research Center in Ibaraki also hope their technique could help rescue endangered species, particularly in cases where only a few individuals remain.
“It’s exciting to see,” says Ben Novak, lead scientist at the wildlife conservation organization Revive & Restore, who was not involved in the work. “I am confident there will be plenty of applications, particularly for conservation purposes.”
Ishiuchi says he and his colleagues were inspired by the Okinawa rubble goby, a fish that can change its sex in certain situations. If no males are present, a female can do this in order to reproduce with the other females. Males can also change sex to female.
This ability to change sex might be useful when it comes to rescuing endangered species, including mammals. There's some precedent in the lab—albeit not intentional. In 2009, researchers reported the accidental birth of a single female pup in a batch of 27 clones created from male mouse cells.
Sometimes the surviving population of a species falls so low that scientists will try to clone those animals. Cloning isn’t perfect—it can be tricky and inefficient, and it creates genetically identical individuals whose offspring might be more vulnerable to disease. But it has helped scientists with efforts to bring some species back from the brink of extinction, including black-footed ferrets and Przewalski’s horse.
Cloning an individual can only replicate its genes, so cloning a male animal will create all male offspring, for example. That won’t help much in the hypothetical situation where only male individuals of a species are left.
Ishiuchi has been working on a way to overcome this challenge by altering the chromosomes in cells. Mammals’ DNA is organized in pairs of chromosomes, including one pair of sex chromosomes. These sex chromosomes are typically XX in females and XY in males.
It’s the Y chromosome that makes mammals male. Ishiuchi and his colleagues have developed a CRISPR-based tool to get rid of it. Their approach targets a section of the Y chromosome that plays an important role in ensuring that, each time a cell divides, the “daughter” cells inherit the Y chromosome.
When the researchers tested their technique—which they call Y-CUT—in early-stage mouse embryos, they found they were able to eliminate the Y chromosome. Treated XY embryos were transferred to surrogate mice, which gave birth to female pups. The effect can be described as a “sex reversal,” say the researchers.
The female pups had XO chromosomes, which means they had one X chromosome rather than the usual two. But this didn’t seem to affect the animals, which grew up healthy and fertile, say Ishiuchi and Matoba.
In a second experiment, the researchers found they could also use Y-CUT to create female clones from male mice.
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