Knocking down a single gene in an adult mouse makes ovaries develop the characteristics of a male gonad and produce testosterone, according to a study published today (December 10th) in Cell. The study suggests that the signal is required to maintain the female phenotype throughout adulthood, and may provide clues to female infertility.

"I think this is a very important finding" identifying a key regulator of the genes involved in sex development, said Blanche Capel from Duke University Medical Center, who was not involved in the research.

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Mathias Treier from the European Molecular Biology Laboratory, lead author of the study, and his colleagues cloned the Foxl2 gene, a transcription factor located on non-sex chromosomes, several years ago. When they knocked out the gene in mice, females began to form ovaries, but later in development, the ovaries degenerated. Since the gene is expressed throughout the lifespan, the researchers wondered whether it would behave the same way in adult females.

In the current experiment, the investigators let the mice develop ovaries normally, and then knocked down the gene once the animals reached adulthood. "We were expecting, honestly speaking, that the oocytes would degenerate," but that the overall female physiology would remain intact, said Treier. Instead, "we got this complete transdifferentiation" from ovaries to testes. Even more surprising, he said, was that "it was the somatic compartment, and not the germ cells, which completely switched to testicular cells," suggesting that the fully differentiated cells had changed to the male differentiated cell type.

Treier speculated that the reason Foxl2 behaves differently during development and adulthood is that it regulates other genes important to organ differentiation. During development, another gene, Wnt4, is thought to be the major signal that suppresses the male program of development. But after the female gonads develop, Wnt4 shuts off. Foxl2's expression throughout the life of a female suggests that it is continually needed in female physiology. (Read more about battling sexual pathways here. )

The change from ovarian cells to testicular cells didn't affect the outward physical appearance of the mice. "They are not producing secondary sexual characteristics. It's just not possible at that stage," said Treier. However, two types of ovarian cells completely switched to male gonadal cells as quickly as 48 hours after the gene was turned off, raising interesting questions about how "all that chromatin remodeling can start to happen in such a short window," said Treier.

A mouse with the ability to change its reproductive organs as an adult also offers researchers a powerful new model. "Because it's in an adult organ, we can dissect molecularly the genetic hierarchy of how testicular cells develop and how ovarian cells develop," said Treier. Foxl2 has also been implicated in female infertility, and researchers think the mouse model could help elucidate how this gene affects hormone production and reproductive capacity in women. Capel agreed. "I think there's more to be learned from this model," she said.

One of the most surprising implications of the finding, said Treier, is that a fully differentiated adult organ has the potential - under the right circumstances - to undergo radical remodeling. "Ten years ago, we thought that when an organ is fully developed it's locked in that state," said Treier. But in light of a slew of recent studies, including Shinya Yamanaka's discovery of four factors that can revert a somatic cell into a pluripotent cell, "I think this dogma is falling," said Treier.


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