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University of Minnesota

A gene that prevents sex reversals

July 20, 2011

David Zarkower, Clinton Matson and Vivian Bardwell.

Research by (l to r) David Zarkower, Clinton Matson and Vivian Bardwell is opening up the secrets of sex determination. Photo: Uriah Mendoza

U researchers discover a gene that keeps testis cells from becoming ovarian cells

By Deane Morrison

Boy or girl?

New parents aren't the only ones who ask that question. Nature asks it in embryonic gonads, and cells answer by turning on genes appropriate to the sex.

But not all answers are final. Researchers have found that certain genes are needed not only to make, but to keep organisms male or female.

Two years ago a team in Germany identified a gene that keeps key cells of the ovary from turning into the corresponding cells of the testis. Now, University of Minnesota researchers have found its opposite number: a gene that keeps key testis cells from turning into ovarian cells.

Loss of either gene causes the cells to switch to the opposite sexual identity, even in adults. The work is published in the journal Nature.

"The presumption had been that the sex determination decision was made in the embryonic gonad, leading to either a testis or an ovary, and the decision was final," says David Zarkower, professor of genetics, cell biology and development and an author of the paper. "That turns out not to be the case in either sex."

Besides showing just how fluid sex determination is, the work reveals a case in which one cell can readily be transformed into another without going through the intermediate step of reverting to a stem cell. These discoveries may thus inform stem cell research, whose goal is to create new types of cells from preexisting ones.

How sex determination works—or not

Throughout the animal kingdom, turning a fertilized egg into a male or female baby requires the work of many genes in different kinds of cells. The scenario Zarkower and his colleagues studied involves cells in the ovary and testis whose job is to nurture and guide stem cells called germ cells into becoming either eggs or sperm.

In the testis, that task falls to Sertoli cells. They control both the development of germ cells into mature sperm and the number of sperm produced. In the ovary, cells called granulosa cells nurture the cells destined to become eggs.

The German team, at the European Molecular Biology Laboratory in Heidelberg, found that if granulosa cells of mouse ovaries lost a gene called Foxl2, they turned into Sertoli cells. That means Foxl2 is crucial for normal female development.

In the current study, Zarkower's team genetically engineered mice to lack a gene called Dmrt1. They found that in male mice lacking Dmrt1, the Sertoli cells of the testes turned into granulosa cells. Not only that, but a second kind of ovarian cell, whose function is to secrete estrogens, appeared in the testes (see photo).

Photomicrograph of mutated mouse testis and normal ovary.

In this photomicrograph, cells of a mouse testis lacking the Dmrt1 gene (main image) have assumed the appearance of granulosa cells (violet) and estrogen-secreting theca cells (green and violet) of a normal ovary (insert). Photo: Clinton Matson

"If Sertoli cells lose the Dmrt1 gene, you get an avalanche of feminization," Zarkower observes. If, say, an environmental toxin should disable the gene in an adult man, the research predicts that cells of the testes would become more female, but outward appearances wouldn't change.

The current study also revealed why loss of the Dmrt1 gene was so devastating to maleness: Dmrt1 works by "turning off" the Foxl2 gene; therefore, in Dmrt1-free animals, the Foxl2 gene has free rein to promote female development. And what is one way Foxl2 does this? Sure enough, the German team found that it turns off Dmrtl.

So what emerges is a portrait of ovaries and testes as arenas where these two genes battle for control of the sexual development of organisms, according to Zarkower and his team. In normal males, Dmrt1 wins out over Foxl2 by virtue of being activated, or turned on, earlier in embryonic development. In other words, it gets the jump on its rival. 

"Dmrt1 is a critical gene for male maintenance," says Vivian Bardwell, a professor of genetics, cell biology and development at the U of M and an author on the paper. "There may be other genes whose loss produces the same outcome. We're looking for other genes that function to maintain maleness and prevent femaleness."

Skipping stem cells

The change from Sertoli cell to granulosa cell (or vice versa) looks like the kind of changes stem cell researchers are trying to cause in order to, for example, generate fresh heart cells by reprogramming skin cells. With current technology, skin cells are first transformed in a petri dish into all-purpose stem cells called iPS cells. 

But if scientists could make that process proceed as simply as the transitions between Sertoli and granulosa cells, "we might be able to shorten the process and do it [in the body]," Zarkower says.

The first author on the paper is Clinton Matson, a postdoctoral fellow at the University. Other U of M authors are Mark Murphy, a research associate in genetics, cell biology and development; and Aaron Sarver, a bioinformaticist in the University's Masonic Cancer Center.

Published in 2011

Tags: College of Biological Sciences, Academic Health Center

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David Zarkower

Vivian Bardwell

Department of Genetics, Cell Biology, and Development

College of Biological Sciences