23 June 2003 4:39 GMT

by Tabitha M. Powledge

Philadelphia - Differences between the male and female brain are brought about by the direct effects of genes on the sex chromosomes, says an endocrinologist, and not solely by hormonal differences during development.

The dogma has been that sexual differentiation results from of a bath of gonadal hormones, chiefly early in development. But evidence is mounting that both sexual and social behavior thought to be characteristic of each sex is also influenced by genes on the sex chromosomes.

Some of these results have emerged from a new model system developed for studying sexual dimorphism in mice, work done primarily in groups led by Arthur Arnold at the University of California at Los Angeles, and Emilie Rissman at the University of Virginia Medical School in Charlottesville.

By deleting Sry - a gene on the Y chromosome that controls the development of testes and other male characteristics - and inserting a copy on an autosome, researchers have been able to breed mice with the same gonadal phenotype but different genetic sex: XX and XY males and XX and XY females.

In these mice, most sexually dimorphic brain and behavioral phenotypes remained in gonadal males and females. As expected, the sexual differences between XX and XY males and between XX and XY females were not evident, indicating that most dimorphic behavior is driven by the hormonal output of the gonads.

However, there were some neuroanatomical differences: a more masculine pattern in some brain areas in XY mice, male or female, than in XX males and females. There are therefore genes on the sex chromosomes that result in some brain cell sex differences, they conclude.

Rissman is also using another approach - knockout mice that lack functioning estrogen receptors (ER) - to sort out the origins of sex-specific behavior. Male ER-knockouts do not display normal masculine behavior, and female knockouts display neither female nor male behavior.

In one experiment, male and female ER-alpha knockouts and wild-type mice were gonadectomized and implanted with testosterone. Drawing on previous evidence that dopamine participates in the development of male sexual behavior, the researchers examined behavior after injecting some of the mice with the dopamine agonist apomorphine. As expected, untreated knockouts showed no mating behavior. Treated wild-type mice of both sexes engaged in typical male sexual behavior, and so did treated male and female knockouts.

ER is therefore not required for male sexual behavior, which can be activated by dopamine, concludes Rissman. Double knockouts - mice with neither ER-alpha nor ER-beta - also respond to apomorphine, she says.

Rissman also reports that the genetic background can modify the effects of knocking out ER-alpha. Exploiting the huge behavioral differences among mouse strains, she and her colleagues crossed mice with and without ER-alpha from different strains. Some knockout hybrids regained sexual activity, suggesting that genetic differences between these strains can modify the steroid requirements for sexual behavior.

What do these findings mean for men? Rissman suggests there may be medical implications for male sexual dysfunction, which is common in men with normal levels of testosterone.

And for women? Genetics textbooks teach that one of the two X chromosomes in each female cell is turned off early in development, achieving X chromosome parity between the sexes. Arnold points out that this inactivation of the X chromosome is known to be imperfect, so many women may live with two doses of X chromosome genes. "What difference does that make in their brains? We don't know," he said.