Jan. 4, 1999 LA JOLLA, CALIF. -- To paraphrase a classic rock anthem, flies missing a gene that affects sexual behavior "can't get no satisfaction" no matter how hard they try.
Now researchers at the Salk Institute for Biological Studies have isolated that gene, called dissatisfaction, and gained clues to how it works in fly brains to affect sexual choice in both males and females.
The results, published in the current issue of the journal Neuron, may represent a significant step toward one day identifying similar genes that influence sexual behavior in higher organisms, including humans.
"Our results are consistent with the idea that sexual behavior is controlled, at least in part, by genes in higher organisms, including mammals. We certainly have to take such an idea seriously," said Michael McKeown, senior author of the study and an associate professor at Salk.
As described in their study, Drosophila, a group of non-pathogenic fruit flies, go through complex, almost ritualistic behavior during courtship and mating. For example, a male will approach a female, and "sing" to her by vibrating his wings, and tapping her with his forelegs. Normal females are fairly willing partners, typically mating after several minutes of appropriate courtship. A "dissatisfied" female, however, "goes beyond frigid, she is aggressively resistant to mating, often kicking the male away," according to McKeown.
Mutant males, on the other hand, retain an avid interest in mating, but attempt to mate with male and female flies almost indiscriminately. Unfortunately for the males, they mate inefficiently because they have difficulty bending their abdomen in the appropriate manner. The name dissatisfaction was chosen for the gene because, "the females are bothered, the males do a lot of work for few or no results--nobody's very happy," says Kim D. Finley, postdoctoral fellow in McKeown's laboratory and first author on the study.
The dissatisfaction protein is a member of a family of proteins called the nuclear hormone receptors. This family of proteins directly controls the expression of key genes, often in response to hormones. Other members of the family include the proteins responsible for response to retinoic acid, thyroid hormone, testosterone and estrogen.
Dissatisfaction is most closely related to a subgroup of the nuclear receptors called the Tailless proteins, found in humans, mice, frogs, chickens and flies. The Tailless proteins are known to be critical guides for development of some parts of the brain. Dissatisfaction is also active in the brain, but in a much smaller number of cells, those that have been implicated in control of sexual behavior in several studies. Therefore, the investigators think that dissatisfaction has a similar but distinct function from Tailless and probably from any gene identified to date.
"If there is a human equivalent of dissatisfaction," says McKeown, "and it's turned on in a very small region of the brain, it's going to be difficult to find. We know that even in flies the genetics of sexual behavior is complicated, and we should expect it to be no less so in humans." In addition to dissatisfaction, at least one other characterized genetic pathway can influence sexual development and behavior in flies.
Dissatisfaction is active in a cell's nucleus and has characteristics of genes that act to regulate other genes. Having isolated the dissatisfaction gene, the investigators can begin to identify which genes it turns on or off. Potential applications of the work include the development of sterilizing agents that work through the dissatisfaction pathway, which might be used to control insect populations.
Genetic pathways that affect sexual behavior are also useful model systems to examine general questions about the interaction between genes and behavior, offering "a back door to the big question of how you use genes to wire up a nervous system that can react to the environment," says McKeown. He points out that mutations in sexual behavior, unlike many other neurological defects, are not lethal to an organism. Therefore, investigators can study the effects of these mutations throughout the organism's lifetime, and eventually, it should be possible to apply the findings to broader questions of neurogenetics and behavior.
Salk co-investigators include Philip T. Edeen, Erin Gross, Nora Ghbeish, and Ruth H. Palmer. The study was done in collaboration with Margit Foss and Barbara J. Taylor at Oregon State University in Corvalis.
McKeown and Taylor were supported by the National Institutes of Health. Finely was supported by the National Institute of Neurological Disorders and Stroke and by funds from the Pioneer Foundation. Ghbeish received predoctoral training grants from the National Institute of Child Health and Development and the Salk Institute Association. Palmer was a Human Frontier Science Program Organization Postdoctoral Fellow.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.
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