| Pheromone Notes #25 News release issued
by Howard Hughes Medical Institute:
Pheromones Control Sex Discrimination
In Mice January 31, 2002
Pheromones Control Gender Recognition
in Mice
Researchers have found the first molecular clues about how a group
of poorly understood chemical signals, called pheromones, enable mice to distinguish
male from female. In knocking out a gene for a pheromone receptor in mice,
the researchers discovered that pheromones appear important for gender recognition.
Not only did the male knockout mice lack aggression toward other males —
because they didn't recognize them as being male — they readily attempted
to mate with both males and females, said senior author Catherine Dulac, a Howard
Hughes Medical Institute investigator at Harvard University.
The findings
by Dulac and colleagues at Harvard were published online January 31, 2002, in
Science Express, which provides rapid electronic publication of select articles
that will appear in the journal Science. Dulac and her colleagues have
a longstanding interest in the vomeronasal organ (VNO), a chemical-sensing structure
found in the nasal cavities of many animals that is anatomically and functionally
distinct from the olfactory system. The VNO, which possesses receptors that respond
to secreted pheromones, is wired to a different part of the brain than the olfactory
system. "It had been widely believed that the VNO controlled both
mating and aggression, such that when the animal received one type of pheromone,
it induced mating and another induced aggression," said Dulac. To better
understand the VNO, the scientists produced knockout mice that lacked an important
ion channel, called TRP2, which was thought to mediate pheromone signaling in
the VNO. Previous studies revealed that TRP2 is found exclusively in the VNO.
"To our great surprise — and, at first, disappointment —
we found that these knockout males were perfectly able to mate with females,"
said Dulac. To understand why this was happening, co-authors Markus Meister and
Timothy Holy performed electrophysiological studies on in vitro preparations of
VNO tissue from the knockout mice. Meister and Holy applied mouse urine —
known to contain a mix of pheromones — to VNO tissue and used multi-electrode
arrays to measure the electrical activity of the VNO tissue. The studies confirmed
that the VNO from the knockout mice did not respond properly to pheromone signals.
Additional physiological studies of the knockout mice revealed that the wiring
of their VNOs appeared normal, ruling out a developmental defect as the reason
why mating behavior persisted in the knockout mice. After the scientists
established that mice with otherwise normal VNOs could not respond to pheromones,
lead author Lisa Stowers, an HHMI research associate, began to study the behavioral
effects of knocking out TRP2. In one experiment, Stowers painted the backs of
male mice with urine and introduced them into the cages of knockout mice. The
knockout mice failed to show aggression toward their new cage mates. "It
is well known that if you put a male mouse in a cage for a while, it establishes
the cage as its territory; and if you put another male in the cage, it will be
attacked," said Dulac. "And this attack relies on detection of pheromones
by the resident male. "Besides this lack of aggression by the knockout
mice, Lisa Stowers observed another very strange thing — the knockout males
tried to mate with the intruder males," said Dulac. "It took us a while
to realize what that might mean," she said. "We theorized that the knockout
male could be hyper-sexed — willing to mate with any animal — or it
might not be able to detect the difference." The scientists solved
the puzzle when they placed the knockout mice in cages with either males or females
and found that the knockout mice attempted to mate with either sex. Additional
studies showed that the knockout mice emitted the same mating-related ultrasound
vocalizations with males and females, demonstrating that a full range of courtship
behavior was affected by the loss of TRP2. "Surprisingly, we found
that by knocking out this receptor, we are in a sense uncoupling the mating behavior
itself and the gender-specificity of the mating," said Dulac. The discoveries
apply only to mice, said Dulac, since pheromone signaling may be different in
other rodents and mammals and is thought to be absent in higher primates and humans.
Dulac emphasized that the TRP2-knockout mouse could have many more pheromone-controlled
behavioral effects that the scientists have not yet observed. "We have probably
seen only the tip of the iceberg," she said. "We still haven't studied
the effects of the knockout in females, and we would like to find out when VNO
function is required to establish normal behavior. One might imagine that there
is a time period during development when the mouse needs to have a functioning
VNO, but after awhile, the VNO is no longer necessary because the animal can rely
on other sensory information." Also, said Dulac, the TRP2-knockout mouse
could enable the scientists to trace the neural circuitry by which pheromone signals
enable the mouse to discriminate sex. Click
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