Making the paper

Catherine Dulac

    Pheromone switch determines female sexual identity in mice.

    Precise descriptions of female mouse behaviour are scarce. When, five years ago, Catherine Dulac and her co-workers began analysing mutant mice that lack proper pheromone processing, she was determined to spend equal time studying the behaviour of males and females.

    The mice were missing an ion channel crucial for the proper functioning of the vomero-nasal organ (VNO), a nasal brain projection that detects pheromones. In 2002, the team published the results of its first work with mice. “That study looked exclusively at male behaviour — somewhat to my despair,” says Dulac, who is based at Harvard University. Mutant males failed to distinguish between males and females for mating. But colleagues in the field continued to ask about the female mutants.

    Then postdoctoral fellow Tali Kimchi, a trained observer of wild-animal behaviour, joined Dulac's group. Kimchi began by placing a normal male together with a mutant female. In a role-reversal, the female tried to mount the male. Astonished, Dulac double-checked that it was indeed a female mouse.

    This revealed an interesting twist in VNO function. In the female, loss of the organ seemed to scramble the animal's sexual identity. This, says Dulac, raised the question “what is the relationship between pheromone detection and knowing who you are sexually?”

    There were two possibilities. Loss of VNO function could disrupt proper brain development of female sexual identity. Alternatively, it might reveal a 'male' behaviour circuit already present in the female brain. To test these theories, Kimchi wanted to compare genetic mutants with animals in which the VNO had been surgically removed. But Dulac was doubtful, because previous experiments that removed the VNO had been inconclusive. Keen observation by Kimchi provided a breakthrough.

    Normally, animals are given one week to recover from surgery, then tested for behavioural changes. But Kimchi noticed that the mice were not moving their whiskers in the usual way when picking up olfactory cues. She discovered blood clots in their noses that blocked their normal sense of smell — an impairment sure to affect mating behaviour. To remedy the problem, she gave the animals three weeks to recover, combined with daily nasal cleaning.

    Whether VNO function was ablated by genetics or by surgery, female mice showed the same high level of male-mating behaviours (see page 1009). These included mounting, pelvic thrusting and vocalizations — all of which occurred without significant changes in the animals' levels of sex hormones. The group concludes that the female brain includes the neuronal connections for male behaviour. Somehow, VNO pheromone detection acts as a switch to turn on female behaviour and/or repress male behaviour.

    In this way, development can have “one common brain organization per species and the difference between male and female is just the trigger”, Dulac says. She would like to find the corresponding “hidden female inside the male”, but it's hard to foresee experiments to test this when males lack the anatomical requirements for birthing and lactation.

    Whether the human brain is similarly wired is hard to say. Humans lack a definitive pheromone system, and human sexuality is not so strongly linked to olfaction. “We are controlled more by visual and auditory cues,” says Dulac. “This is why we have something called pornography.”

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    Catherine Dulac. Nature 448, xiii (2007). https://doi.org/10.1038/7157xiiia

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