|Mapping the Most Primal Sense|
|Odorant receptors and scent discrimination in Drosophila|
Edward R. Winstead
August 18, 2000
Scientists have identified virtually the entire set of odorant receptors in the Drosophila genomegenes whose receptors are the fruit fly's connection to the world of smell. In 1999, three groups of researchers independently identified a total of 18 receptor genes using the incomplete genome sequence. An analysis of the complete sequence revealed that the actual number of receptors appears to be 60.
Now, two laboratories are reporting that the logic of smell discrimination is fundamentally similar in the fly and the mouse: Olfactory information is relayed from the periphery to fixed locations in the brain; different odors activate different regions of the brain, allowing the mouse or fly to distinguish among smells. The current findings suggest that Drosophila may be a useful model for understanding smell in humans.
"The fly is basically a miniature mammal when it comes to smell," says Leslie Vosshall, a researcher at Columbia University College of Physicians and Surgeons in New York. "The anatomy and organization of fly and mammalian olfactory systems are quite similar." Vosshall works in the laboratory headed by Richard Axel, a member of Howard Hughes Medical Institute at Columbia. In the early 1990s, Axel co-discovered one of the largest gene families ever identifieda group of odorant receptor genes in rats.
Axel's group estimates that humans have between 500 and 1,000 olfactory receptors and can recognize 10,000 unique scents. The fact that so much of the genome is devoted to smell indicates its importance in the lives of most animals. Being able to differentiate among many different odors instantly and efficiently requires clever biological tricks, and most of these tricks are a mystery.
In contrast to mammals, insect species use specialized olfactory systems to identify a relatively small set of odorsthe ones that are relevant to the species' particular ecological niche. Drosophila melanogaster, for example, has a keen sense for the odor of rotting fruit yet disregards the fragrance of a shrub favored by its cousin, Drosophila sechellia.
Success with genomics
Despite years of searching, no one has been able to locate the fly's receptor genes until now. Even with the "complete" genome sequence, finding the 60 Drosophila receptors proved to be a challenge. The genes have structural features in common, but the sequences are diverse and they look nothing like odorant receptors that have been identified in humans, rodents, or the soil worm C. elegans. Furthermore, the genes reside throughout the genome rather than in geographical proximity.
"The Drosophila odorant receptors are very rare and very different from each other," says Vosshall, who spent the last five years trying to identify 12 fly receptors. "Probably ten groups have been struggling worldwide to get these genes for 25 years. In the end, the only way we got them was genomics."
In 1999, before the sequencing phase of the genome project was complete, researchers identified a total of 18 odorant receptors using early batches of data. (A few years earlier, a single odorant receptor had been found using traditional gene-hunting methods.) The remaining receptor genes were discovered during a functional analysis, or annotation, of the genome. Working together last December, fly biologists, bioinformaticists, and genome scientists used computer database searches to identify all but a few of the 60 receptors.
Odorant receptors bind with odor molecules in the environment as the first step in the process of smell differentiation. The challenge facing researchers is to explain how that binding step is translated into olfactory information that is recognized and interpreted in the brain. Two groups, one at Columbia University and one at the Massachusetts Institute of Technology, have recently published papers describing aspects of the process in Drosophila.
In a recent issue of Cell, Richard Axel's group reports that a central feature of the Drosophila olfactory system is a sensory map in the brain. A switchboard of sorts, the map represents the activity of specific odorant receptors. Unique spatial patterns are subsequently recognized and interpreted by a higher-order mechanism in the brain.
A second group, led by Andrew Chess, of the Whitehead Institute for Biomedical Research and the biology department of the Massachusetts Institute of Technology, also reports that a sensory map in the fly brain appears to be the basis for smell discrimination in Drosophila. Projections from individual olfactory neurons expressing a given receptor converge at fixed locations in the brain, creating a topographical map. In this model, too, projections are recognized and interpreted by some unknown feature of the nervous system. A paper describing the research appears in the current issue of Nature Neuroscience.
"We found that there was a convergence of projections and the formation of a topographic map," says Chess. "In this respect the fly is similar to the mouse." About six years ago, researchers demonstrated that a sensory map and projections were involved in mouse olfaction.
In mammals and now in flies, it appears that each olfactory neuron expresses only a single receptor. All olfactory neurons that express a single odorant receptor converge in the brain, creating synaptic structures called glomeruli. The antennal lobe of the fly brain contains 43 distinct glomeruli, whose position and size appear to be the same in different flies, according to Vosshall.
How it is that a neuron chooses to express one of a thousand odorant receptors is a mystery, notes Chess. How these neurons come to be appropriately connected to the rest of the nervous system is also a mystery.
Complexity and simplicity
Axel's laboratory is interested in the fly as a model organism for its complexity as well as for its simplicity. As Vosshall points out, the fly is a free-flying organism that has a brain and makes important decisions based on olfactory cues. Moreover, flies can learn and be trained to avoid certain smells. Drosophila may be better suited to certain smell experiments than another organism whose genome has been sequenced, the soil worm C. elegans.
The logic of the worm's olfactory system is different from that of the mouse. As noted in the Cell paper, a family of 1,000 receptor genes in the worm is expressed in only 16 pairs of sensory cells. And each neuron expresses multiple odorant receptors. "It's fair to say that the fly system is closer to the mouse than to C. elegans," says Chess.
Only further experiments will reveal whether the fly is a particularly useful model of human olfaction. If the fly proves to be a useful model, Axel's group may use the insect to study the connection between smell and memory. "One unexplored area," says Vosshall, "is the role of odor as a powerful trigger of memory. Why do some odors associated with specific events in life cause a rushing back of memories?"
Axel's group proposes in the Cell paper that the organization and functional logic of olfactory sensory perception appears to have been maintained over 500 million years of evolution. The conservation of mechanisms in the olfactory system throughout evolution, the researchers conclude, indicates that the system provides "an efficient solution to the complex problem of recognition and discrimination of a vast repertoire of odors in the environment."
In recent months, members of the fly community have agreed on a unified naming system for the odorant receptors. Different laboratories had identified and named some of the same genes differently, resulting in a bit of confusion in papers and at scientific meetings. The complete list of the genes and their old and new names also appears in Cell.
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