Fwd: Sexual ID switch is found

From: Wade T.Smith (wade_smith@harvard.edu)
Date: Fri Feb 08 2002 - 00:58:03 GMT

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    Sexual ID switch is found:
    Research finds that mice make love not war

    By William J. Cromie
    Gazette Staff


    In Catherine Dulac's laboratory, male mice are acting strangely. They do
    not attack other males that invade their territory. They will even try to
    mate with the invaders.

    These animals are living examples of a sexual switch controlled by a gene
    discovered by Dulac and her colleagues at Harvard University's Department
    of Molecular and Cellular Biology. Called TRP2 (pronounced "Trip 2"), the
    gene produces a signaling protein that regulates both aggression and
    sexual behavior.

    The males can, of course, distinguish other males from females by their
    looks, size, and smell. But with TRP2 switched off, no matter what their
    senses tell them, the males will not fight for their territory, and they
    will make love to male intruders as quickly as they will to females.

    "We are totally surprised that a single gene has such a profound effect
    on behavior," admits Dulac. "In humans, such basic behaviors are unlikely
    to be explained by the activity of only one gene. Using the mouse as a
    model for humans, however, can help us to better understand how the brain
    influences behavior through input from sensory systems."

    The input in this case is scent. Humans respond to odors that waft
    through the air and send messages to the brain via receptors at the back
    of the nose. But mice, dogs, cats, and most other mammals also rely on a
    completely separate system. The front of their noses, or mouths, contains
    a double pit and tubes that make up the vomeronasal organ (VNO), which
    brings smells, via a separate pathway, to a different part of the brain.

    VNO receptors are stimulated only by direct contact with pungent scent
    sources such as skin, sweat, or urine. These sources release molecules
    known as pheromones, which excite nerve endings that connect with
    cerebral regions involved in controlling sex and aggression. It's these
    signals that TRP2 turns on.

    Humans lose an organ

    Vestiges of the VNO linger in humans. Its pits and tubes, along with
    nerve endings reaching to the brain, appear in embryos. But after several
    weeks the organ shrinks away.

    Some perfume makers would like us to believe that their fragrances can
    awaken this extinct sense. But "it's lost to evolution," Dulac says. Even
    apes and gorillas, our evolutionary first cousins, no longer rely on it
    to find mates, she adds.

    Dulac should know. For five years, the nosey 38-year-old neuroscientist
    has studied genes linked to the VNO. None of them function in humans. Two
    years ago, she and her colleagues discovered the TRP2 gene in mice. It
    produces a protein that opens a channel that permits pheromones to
    stimulate the VNO. Block that gene, thought Dulac and her team, and you
    alter the cascade of chemical foreplay that leads to mating.

    Lisa Stowers, a postdoctoral fellow in Dulac's lab, conceived and
    conducted experiments to test this idea. A former postdoctoral fellow,
    Georgy Koentges, created mice lacking a TRP2 gene.

    "We expected these so-called knockout mice not to mate," Dulac recalls.
    But the mutant rodents were as sexually active as wild mice. "It was a
    big disappointment," Dulac admits.

    Then the team decided to test aggression. When put in a cage, a normal
    male mouse stakes out a territory, then defends it vigorously against
    other males. But knockout mice have no fight in them.

    To eliminate the possibility that invading males spark fights merely by
    their presence, rather than by releasing pheromones, some of the
    intruders were castrated. Then the experimenters marked them with a drop
    of urine from intact males. Wild mice attacked the castrated intruders,
    but TRPless mice did not.

    Not only did the knockout mice not attack scented and castrated males,
    but they mated with them. When females in heat were added to their cages,
    TRPless males spent as much time trying to mount the males as the females.

    That leads to only one conclusion: mice without a TRP2 gene lose the
    ability to select whom they should mate with. Their default behavior is
    to mate with everyone.

    With the help of Markus Meister, Jeff C. Tarr Professor of Molecular and
    Cellular Biology, and postdoctoral fellow Timothy Holy, the team designed
    and performed another experiment. Male mice respond with a high-pitched
    sound when confronted with a desirable female. It's like a "hubba hubba"
    that is inaudible to humans. TRPless mice emit this signal whether they
    meet a female or male. This reinforces the conclusion that the mutants
    have lost the ability to tell if they're with a male or female.

    "The pheromones are not mating triggers as we first believed," Dulac
    notes. "They don't tell mice when to mate but with whom. Knocking out the
    TRP2 gene abolishes pheromone-evoked aggression while courtship is
    indiscriminately displayed toward males and females. It's a striking and
    profound behavioral change."

    Stowers, Dulac, and their colleagues will publish the complete results of
    their study in the Feb. 21 issue of Science magazine.

    The female side

    So what happens to females who lose their TRP2 gene? "We're trying to
    find out," Dulac answers. "Mating and aggressive behavior in normal
    females has not been as well studied as that of males. We're looking at
    what hormonal changes are involved. We need to pinpoint normal behavior
    before we can determine how it will be changed by a key missing gene."

    Lack of knowledge about the nature of pheromones also clouds the window
    of understanding. Dulac counts 400-500 different pheromone receptors in a
    good animal nose. Singly or in combination they must be able to recognize
    thousands of scents. However, no one has yet been able to determine the
    structure and function of even a single pheromone.

    Studies of pheromones that guide insect and fish behavior reveal that
    these molecules are highly species specific. Not only the chemical makeup
    but the amount of a pheromone can alter the message it conveys, such as
    the identity of the animal that marked a certain tree or bush with its

    Despite the lack of a direct human connection, plenty of practical
    reasons exist for us to learn more about pheromones. The animal husbandry
    industry has a huge interest in sniffing out such knowledge. Compounds
    that stimulate or block pheromones could enhance or hinder reproduction
    and aggression among food and farm animals, zoo residents, and pets.

    Under certain conditions, for example, pigs become very aggressive and
    start biting each other for no apparent reason. Such behavior creates an
    obvious market for a pheromone pacifier. Dog and cat owners would
    appreciate a way to calm their pets during long trips. Canines and
    felines mark their territory with pheromone-laden urine. Packaged in a
    spray can, such scents could make them feel more at home in strange

    Zookeepers would love to create a pheromone potion that would induce
    mating among pandas and other endangered species with a disinterest in
    mating. Scientists in Asia are experimenting with odors that make
    elephants more responsive to each other. So far, they've isolated an odor
    that makes pachyderms raise their trunks in a key display of courtship
    behavior. "It's not a very profound result," Dulac sniffs.

    Dulac is not as interested in such practical applications as she is in
    the basic biology of these mysterious molecules. "Discovering a brain
    circuit that controls the determination of sex, even only in mice," she
    says, "is exciting because it links sensory stimulation (the outside
    world) to behavior (the inside world)."

    "Smell is surer than sight or sound." - Kipling

    Copyright 2002 by the President and Fellows of Harvard College

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