Defective Sperm in Mice Offer Clues to Infertility in Men Council research is shedding light on possible causes of—and suggesting possible treatments for—male infertility. The findings are also pinpointing potential targets for developing a reversible male contraceptive.  Diagram of a normal mouse sperm.
Illustration: Evan Read |
The discovery stemmed from research at Hermann Stellar’s lab at Rockefeller University—home as well to the Council’s Center for Biomedical Research—where scientist Holger Kissel developed mice lacking a specific gene for an unrelated study. Unexpectedly, he noticed that the male mice were infertile. To learn why, Kissel turned to Council cell and molecular biologist Gary Hunnicutt, who studies the mechanisms that enable sperm to swim and fertilize eggs. This expertise made Hunnicutt especially qualified to investigate the mystery of the sterile mice, which produce the same number of sperm as normal mice, but cannot sire offspring. Hunnicutt found that the mice were sterile because their sperm
had severely bent tails; had abnormally formed mitochondria—the energy-producing structures in a cell; and were unable to swim. The sperm also retained large droplets of organic material on their tails, resembling a human condition associated with infertility known as “droplet sperm.” What was not known was why eliminating the specific gene in Kissel’s experiment created so many abnormalities. The answer appeared to lie in the uniqueness of the spermatozoa. “Sperm, unlike other cells, must change function as they
encounter many different environments in both the male and
female reproductive tracts,” explains Hunnicutt. “Other cells alter their function by making a new set of proteins, while sperm bring about change by rearranging existing proteins into new patterns
of interaction.” A ring-like structure on the sperm tail called the annulus is thought to be the gate that separates the tail into two distinct “protein compartments.” Proving this has been difficult because the composition of the annulus was unknown. However, Hunnicutt recognized that the sperm tails were bent where the annulus ought to be, and microscopic techniques revealed that the annulus was indeed missing. 
Top: (left) Normal mouse sperm; (right) Mutant sperm with tail doubled back. Center: Annulus (arrow) between midpiece and principal piece of sperm. Bottom: Sperm with missing annulus.
Photo credit: Angela Klaus/American Museum of Natural History |
“These mice have elevated the importance of the annulus because without it sperm tails cannot remain straight,” say Hunnicutt. “Plus, in comparison studies using sperm with or without an annulus, we can finally test whether indeed the annulus works as a protein gate.” Additionally, because sperm are so profoundly affected by this gene deletion, the proteins normally made by the gene are now potential targets for the development of novel reversible male contraceptives. Contraceptive approaches that seek to stop sperm production work by manipulating the male hormone, which can result in unwanted side effects, but tweaking a specific sperm protein to disable it might inhibit fertility without negative side effects. “What we are trying to identify is a functional ‘off switch’ on the sperm, which could be flipped off when contraception is desired and back on when it isn’t. Our current findings are taking us a step closer to identifying this switch and understanding how sperm become cells capable of fertilization.” That knowledge, in turn, may further medicine’s understanding of human male infertility, and potentially improve the fertility and quality of sperm in infertile men. This research was partially funded by the National Institutes of Health. (Return to issue contents)
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