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Thinking 'Bout Sex

By Constance Holden
February 20, 2006

What's on your mind?
The male rat brain (above) shows abundant expression of Sry gene, particularly in the substantia nigra (SN) and mamillary bodies (MMB). The female brain (below) lacks the gene.

Credit: Eric Vilain

For the past 50 years, it's been assumed that differences in male and female brains are generated by the doses of sex hormones they get before birth and throughout life. Now scientists have fingered a gene on the Y chromosome that they say directly molds the brain and behavior independent of the action of hormones.
In 1990, scientists identified a gene called Sry, which causes testes to form. Because that gene directly affects the developing embryo's gonadal ridge tissue, scientists have suspected that Sry and other Y chromosome genes could shape additional tissues, including brain cells.

In the new study, a team led by geneticist Eric Vilain of University of California, Los Angeles (UCLA), determined that Sry proteins are expressed in the same brain cells that put out tyrosine hydroxylase (TH), the substance that synthesizes the neurotransmitter dopamine. To find out if the Sry gene was directly influencing brain function, researchers reduced Sry expression by injecting an "antisense" stretch of DNA directly into the brains of 13 male rats. They targeted the substantia nigra, a brain area implicated in Parkinson's disease, which is rich in dopamine neurons and also has high levels of Sry protein. The injections were done on one side of the brain so the other side could serve as a control for each rat.

Sry is crucial for dopamine-secreting neurons to function normally, the researchers report today in Current Biology. The injections downregulated Sry and slashed the production of TH by 50%. The resulting loss of dopamine was clearly evidenced in the rats' behavior: For example, when put in an upright cylinder, rats tried to climb out, but they were much less likely to use the paw on the side affected by the Sry reduction.

The study is "the first to identify a specific sex chromosome gene that has a sex-specific effect on the brain," says UCLA neuroendocrinologist Arthur Arnold (who was not involved in the study). The "paradox" of the paper is that "females are not deficient for the kinds of things Sry does" in males, he says. In other words, the Sry gene appears to compensate males for their lack of estrogen, which in females controls TH. "The results open the way to a whole new series of studies to identify the role of Sry in several brain regions," Arnold says.

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