In an ingenious study of severely uncoordinated fruit flies, scientists at the University of California, San Diego have obtained the first molecular hints of how humans and other complex organisms hear, maintain their balance and sense touch.
In the March 24 issue of Science, the researchers at the university's Department of Biology and Howard Hughes Medical Institute report their discovery of a gene in Drosophila that, when altered, disrupts the molecular functioning of the fruit fly's mechanoreceptor cells. This results in flies that are unable to hear and sense the world around them, and are so uncoordinated that without help from the researchers they quickly die.
"You literally have to hand-feed them, put food in their mouths, because they're so uncoordinated that they just can't function in any other way," said Richard G. Walker, a postdoctoral researcher at UCSD and the first author of the study. "It's a lethal mutation, because once they come out of their pupal cases they are so uncoordinated that they just fall into their food, which is kind of sticky, where they get stuck and die."
Scientists have known for the past 15 years that mechanical energy in the form of sound and touch can be transformed by tiny mechanoreceptor cells into chemical and electrical signals that are processed by the brain to hear, sense touch, maintain balance and determine the position of one's limbs in space. Many of these cells, which are found in vertebrate and invertebrate animals, consist of tiny hair-like structures that, when deflected, open ion channels in the cells, triggering the release of neurotransmitters, which then produce electrical responses in the brain.
"The mechanical senses are conserved through evolution, from the tiniest organisms to humans, because they all perform this critical function, which is to respond to mechanical stimulation," said Charles S. Zuker, a professor of biology who headed the study. "Our enjoyment of wonderful symphonies is nothing but the conversion of mechanical energy into electrical signals by the cells in our inner ear."
What scientists have not known is how genes affect the detailed molecular processes in these mechanoreceptor cells. Such cells are typically small and relatively scarce, making it difficult for researchers to accumulate enough material for biochemical studies. But in Drosophila, the bristles of the mechanoreceptor cells on the insect's thorax are especially large and prominent, making them amenable for biochemical and electrophysiological studies. Because so many of its genes have been identified and mapped, the fruit fly is also an ideal organism on which to conduct genetic studies.
To conduct the study, Walker first screened 27 strains of Drosophila with genetic mutations that made them severely uncoordinated. These mutants, which were isolated six years ago by Maurice Kernan, a postdoctoral researcher in Zuker's lab who is now at the State University of New York at Stony Brook, are thought to have a variety of mutations that prevent their brains from receiving signals from their mechanoreceptor cells.
However, Walker wanted only those mutants with defects in the mechanoelectrical transduction pathway itself. He found them by measuring the electrical currents of their mechanoreceptor neurons when the hair bristles of the cells were deflected slightly, an action that in normal insects produces a small electrical current. The cells are so sensitive that a movement that deflects the bristles only a small fraction of a micrometer can be sensed by the brain.
After Walker found three strains that produced little or no electrical current, dubbed nompC for "no mechanoreceptor potential C," he identified a gene, encoding a novel ion channel, that when put into nompC flies restored the mutants to normal. Aarron T. Willingham, a graduate student working in Zuker's lab, tied the defects to mutations in this gene, confirming nompC's identity.
"Once they cloned nompC, everything was clear," said Peter G. Gillespie of the Oregon Hearing Research Center and Vollum Institute at the Oregon Health Sciences University. "nompC is definitely part of the fly transduction channel, either the pore itself or a principal component. This work has enormous significance as it suggests that one could find other mechanotransduction channels by looking for relatives of nompC. Identifying any protein that serves within any mechanical transduction apparatus has been exceptionally difficult. But here we have a clear answer."
The UCSD researchers found a homologous, or functionally similar, protein produced by a similar gene in the roundworm C. elegans. They suspect that similar genes and proteins are found in humans and other vertebrate organisms that have retained the same genetic and biochemical machinery as Drosophila and C. elegans through evolution.
"If there's one thing we've learned over the past 80 years, it's that model organisms like Drosophila are wonderful engines of discovery," said Zuker. "They not only allow us to efficiently focus on problems that are hard to track in higher organisms, they also recapitulate much of the same biology as more complex forms. In essence, we are nothing but a big fly."
He and his colleagues believe their discovery could have application in understanding and treating hearing loss, which is estimated to affect some 30 million Americans.
"As hard as it may be to visualize, there are very strong developmental and physiological parallels between mechanosensation as done by fly bristles and by the human inner ear," said James W. Posakony, a biology professor at UCSD. "So it is quite possible that a human version of this channel protein exists and has a major role in how we hear. This would be of extreme importance in understanding both hearing and deafness in humans."
"Hearing loss is a major medical problem in industrialized countries, because hearing loss comes in many different shapes and forms," said Zuker. "Many are inherited and many are due to abuse. It's very likely that both types of human disorders are intimately tied to defects in the ability of these cells to perform. So understanding the mechanism of mechanosensory signalling can produce some very important insights into how to treat, prevent and diagnose hearing disorders."
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