March 24, 2000
Studies of Clumsy Flies Yield Molecule Important in Balance, Hearing
Researchers studying uncoordinated fruit flies have identified a
central component of the sensory machinery that underlies balance,
touch and hearing. The discovery helps explain how mechanical sound
waves are converted into nerve impulses — a medically important
question since nearly 30 million people suffer from hearing loss due to
defects in this sensory machinery.
In an article published in the March 24, 2000, issue of the journal
Science, the researchers reported experiments in which they
precisely twitched the microscopic bristles of uncoordinated mutant
flies and measured the ensuing electrical activity. The scientists
identified a molecule called an ion channel, which is somehow pried
open when a bristle is deflected. When the channel opens, potassium and
sodium flow into a neuron, causing an electrical "depolarization" that
triggers a nerve impulse. Ion channels are typically large,
teepee-shaped proteins that nestle in the cell membrane and control the
passage of ions into the cell.
"Previous researchers studying sensory hair cells in the ear
developed a very powerful and elegant model of how mechanoreception
might work," said Charles
Zuker, an HHMI investigator at the University of California, San
Diego. "In this model, there is a channel in the sensory cell membrane
that opens when a mechanical stimulus impinges on it — creating a
near-instantaneous neural signal. However, these channels are so rare
in each cell that they had never been isolated."
In an effort to pinpoint such channels, Zuker's postdoctoral fellow
Richard Walker set out to study mutant fruit flies that were defective
in mechanoreception. The mutants had been isolated in earlier studies
by another of Zuker's postdoctoral fellows, Maurice Kernan.
"These mutant flies have virtually no sense of balance, so they just
fall over when they try to walk," said Walker. "They also frequently
cross their legs, which is something normal flies never do."
Using a measurement technique developed by Kernan, Walker first
snipped off the tip of a fly bristle, which is about a hundredth the
diameter of a human hair. He then slipped a superthin fluid-filled
hollow glass pipette over the bristle.
By precisely moving the pipette, he found that he could bend the
bristle. Since both the pipette and the hollow bristle were filled with
liquid, Walker could measure the electrical current transmitted through
the bristle from the fly neuron to which it attached.
Such studies coupled with genetic analyses revealed that several of
the flies shared mutations in a particular gene, which Zuker and his
colleagues called nompC, for "no mechanoreceptor potential-C."
The mutant flies either lacked the transduction current or showed
currents that indicated rapid adaptation to mechanical stimuli.
"We knew that these two phenotypes had to occur in the same gene, so
it seemed very likely that this gene was critically involved in the
transduction process," said Walker.
When the scientists isolated the nompC gene and analyzed its
structure and function, they discovered that it closely resembled genes
for other ion channels in flies and vertebrates, including humans.
Aarron Willingham, a graduate student in Zuker's laboratory, then
explored whether a similar channel could be found in the roundworm,
C. elegans, which had been used in some previous studies of
mechanoreception. Willingham attached a fluorescent reporter gene to
the worm homolog of the nompC gene and inserted it into the
worms. The experiments indicated that the worm nompC gene was
specifically expressed in the neurons that were the worm counterparts
of the fly mechanosensory neurons.
"Taken together with the earlier findings that the responses of fly
bristles are very similar to those of human hair cells, the discovery
of nompC's role is likely to impact studies of mechanoreception
in other systems, including vertebrate hair cells," said Zuker.
"Since sensorineural hearing loss is such a major medical problem,
any advance towards understanding even the most fundamental features of
the mechanosensory system can have a significant impact in the
development of new therapies," he said.
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