Hitting the "Maleness" JAKpot

We all learned it in grade school: Boys have a Y chromosome, and girls don’t. A genetic switch turns on maleness or femaleness. But actually, it’s not so simple. A developing embryo’s search for its sexual destiny follows a long and windy road. “I don’t like the term sex determination,” said Mark Van Doren, an Assistant Biology Professor at Johns Hopkins University, because “it implies one moment. But it’s actually a very long process.”

The process starts with the germ cells that have the unique ability to create a new organism; male germ cells go on to produce sperm, while female germ cells produce eggs. But how is the sex of the germ cell determined? In Drosophila fruit fly experiments published in the July 28 issue of Nature, Van Doren and his colleagues found that when activated by neighboring tissue, a certain chemical pathway—JAK/STAT—develops male, but not female, germ cells.

By the time a young germ cell starts down the road to sexual identity, its gonad neighbors—called somatic cells—are already different in males and females (male somatic cells express a specific gene called doublesex). And previous studies had shown that these differentiated neighbors somehow influence the germ cell’s sexual destination. As Van Doren explained, “Germ cells can’t do it on their own...they need a specialized soma” to tell them how to develop.

To find out how exactly the germ cells are influenced by their somatic neighbors, Van Doren’s team first looked at fruit fly gonads with a male germ cell surrounded by male somatic cells. In these situations, the JAK/STAT chemical pathway was always activated—that is, a specific molecule set off a chain of reactions that ended in the expression of a protein called “STAT” in the germ cell. They knew STAT was expressed because they had added molecules with fluorescent tags to find and bind to STAT proteins, in effect “lighting them up” for anybody peeking through the microscope. For the next set of experiments, this fluorescent presence would indicate germ cell maleness.

Their next step was to see what would happen to the sex of the germ cell if they broke one of the links on the reaction chain. When they inhibited JAK/STAT in gonads with male germ cells surrounded by male somatic cells, the germ cells no longer expressed the STAT protein and thus, as Van Doren said, “Male germ cell identity was lost.”

Their most remarkable experimental manipulations, however, observed the function of JAK/STAT in female germ cells. They placed female germ cells in surrounding tissue that expressed the doublesex gene (and was therefore male). These male somatic neighbors triggered the JAK/STAT pathway, telling the female germ cells to express the STAT protein. “We took a female and made it look male,” Van Doren said, “And that’s really the wow factor.”  

Van Doren and his team have now shown that activation of JAK/STAT leads to the development male germ cells and thus, a walk down the road to Spermville. But, he stressed, this doesn’t mean females take the path of least resistance. Soon the biologists will look for somatic signals that point to Eggdom instead. Whether flies or humans, though, these signals are just early signposts along the long and torturous road to true sexual identity.