Female hormones circulating in the brain determine masculine behavior, at least in mice. Estrogen--the quintessential female hormone responsible for regulating the reproductive cycle--turns lady mice into wannabe male mice when it is allowed to penetrate the brain during development, according to new research.

Neuroscientist Julie Bakker of the University of Liege in Belgium and her colleagues proved this in the course of solving one of the longstanding riddles of brain development. Although it had long been known that a certain protein--alpha-fetoprotein (AFP)--plays a key role in mouse brain development by binding to estrogen, it was unclear whether AFP facilitates the development of female brains by carrying the hormone or simply by blocking it from entering the brain.

The scientists used female mice incapable of producing AFP and set them loose in a Plexiglass aquarium with a sexually active male. To give them extra incentive to mate, they also received injections and capsules of female hormones. But, unlike their wild cousins, the AFP-deficient mice showed little interest in the male's advances and their brains had fewer cells devoted to producing certain chemicals critical to reproduction, just like males. Furthermore, when placed in a cage with a sexually receptive female, the mice without AFP tried to mimic their male counterparts by mounting the female and engaging in pelvic thrusting.

These observations still didn't constitute definitive proof that AFP helped female mice stay ladylike by blocking estrogen, however. So the researchers prevented AFP-deficient mice from being exposed to estrogen while still in the womb. Without AFP and without estrogen during brain development, these mice proved just as behaviorally female as their wild cousins, the researchers report in the February issue of Nature Neuroscience. In addition to revealing that it is the lack of estrogen that makes the brains of female mice feminine, the findings indicate that it is the presence of the hormone that makes male mice behave as males.

In primates, including humans, androgen--not estrogen--plays the key role in making men's brains masculine and AFP does not bind to estrogens. But the appropriately named sex hormone binding globulin (SHBG) may play a similar role to that of AFP, Bakker notes, keeping women feminine and allowing baby boys develop masculine behavior.