Potential Male Contraceptive Target Discovered by Salk Scientists
La Jolla, CA – The first gene to control male fertility without affecting sexual behavior or physical appearance has been identified by Salk researchers. The study, appearing in the current Nature Genetics, demonstrates that a certain genetic mutation eliminates sperm development in male mice. It has no effect on females.
"The mutation appears to specifically knock out sperm formation without altering mating behavior or 'feminizing' the mice physically," said Salk Professor Tony Hunter, lead author of the study. "That's what makes it exciting as a potential target for a male contraceptive."
The development of a male pill has been dogged by side effects including loss of libido and physical changes including breast development.
In addition to its potential in developing a male contraceptive, the mutation in the gene encoding Kit/SCF-R may point toward ways to protect male fertility during cancer chemotherapy by temporarily suspending sperm formation
"The most exciting and surprising aspect of our findings is certainly the specificity of the defect in the mutant mice. There seems to be no other observable effects of the mutation in Kit/SCF-R than the block in sperm maturation," said Peter Blume-Jensen, a postdoctoral fellow in Hunter's laboratory and first author on the study.
Kit/SCF-R is a signaling molecule. Like a satellite dish, it perches on the membrane, the film that surrounds a cell, and forms a barrier between it and the exterior environment. "The Kit/SCF-R is stimulated by a specific growth factor, a hormone-like molecule called stem cell factor, that relays its cues to the cell interior," continued Blume-Jensen.
Removing Kit/SCF-R completely is lethal. "This is because Kit activates many molecules within the cells, some of which exert specific functions essential for life. For example, we know that this gene is involved in blood cell development and pigment formation. We specifically disabled it from activating only one molecule required for male fertility, while all other molecules are still activated," said Blume-Jensen.
Through elegant and extensive genetic manipulations, the Salk team created mice with a normal Kit/SCF-R gene except for a small mutation affecting its ability to activate only one molecule.
"It's important to note that these mutants display normal male behavior for mice," said Hunter. "They mate with females and, after mating, are aggressive toward other males."
And, unlike castrated mice, the Salk mutants are physically normal.
"Castrated mice develop pockets of body fat, their muscles atrophy, and they are unable to defend themselves against other males," said Blume-Jensen. "We don't see any of these effects in the Kit mutants, suggesting that it should be possible to develop agents that block one particular aspect of the Kit action – sperm formation – without inducing feminization or other undesirable effects. Provided that our findings translate to humans, such agents could be ideal male contraceptives."
Kit/SCF-R encodes a type of protein called a tyrosine kinase receptor. Tyrosine kinases were shown by Hunter about 20 years ago to be important mediators of cell growth, and since then, have been implicated in many physiological processes.
The Kit/SCF-R mutants were created through a process that permits the introduction of discrete targeted mutations, in contrast to existing standard "knockout" technology, in which entire genes are removed. Since it allows for a more refined examination of gene activity than knockout technology, the investigators believe this technique will become the gold standard for the coming decade.
Additional Salk authors include Guoqiang Jiang, a postdoctoral fellow in Hunter's laboratory; Professor Robert Hyman; Assistant Professor Kuo-Fen Lee; and staff scientist Stephen O'Gorman. Blume-Jensen is a Special Fellow of the Leukemia Society of America, Lee is a Pew Scholar, and Hunter is a Frank and Else Schilling American Cancer Society Professor. The work was supported by the National Institutes of Health.
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.