Mice that can no longer detect pheromones because of a single gene deletion cross the boundaries of typical gender behavior.

A female mouse shows surprising behavior by pursuing another female.

Female mice do not usually initiate sex or mount their partners. Yet a subset of mutant females, studied by HHMI investigator Catherine Dulac and her Harvard research team, has upended the world of lab mouse intercourse.

Dulac's study suggests that sexual behavior in mice is not exclusively connected to inherent differences in the male and female brain. Instead, she found that gender roles become strikingly fluid when the mice are unable to detect pheromones.

Mice detect pheromones through a chemosensory organ called the vomeronasal organ (VNO), located in the nasal cavity. The VNO requires a specific ion channel called TRPC2 to function. When Dulac and colleagues Dr. Tali Kimchi and Jennings Xu bred TRPC2 knockout male and female mice, the mutant mice ignored chemical cues that generally produce gendered behavior. Male knockouts showed a lack of aggression toward other males, and mounted male and female mice indiscriminately. Female knockouts exhibited typical male behavior, such as attacking intruding males, pelvic thrusting, and soliciting sex by using their noses to poke other mice in the rear.

"There's a major finding here," says Dulac. "Sex-specific behaviors were assumed to be controlled by sex-specific neurons. We found that the brains of animals in a given species may have male and female components controlled by a switch. That switch is sexually dimorphic and modulated by pheromones."

Dulac is careful to clarify that olfactory cues impact sexual behavior in mice much more than in humans. Like other primates, people lack vomeronasal organs and perceive the world mostly through vision. But Dulac insists that focusing on the fact that her study pertains to olfaction is missing the point. It is the switch mechanism, independent of the sensory modality, that could apply to several other species, she says. "We are shattering the dogma on the male and female brain and the major importance of testosterone."

Dulac hopes that her findings will provide a fresh outlook for everybody in her field. Next, she plans to focus on whether the male knockout mice demonstrate typically female behavior. "There are some species of rodents in which the father exhibits parental behavior," she explains. "Maybe there's something there."

Photo: Dulac Lab