CHAMPAIGN, Ill. — A team of proteins vital to fertility because of their ability to send signals that allow sperm to pass through an egg membrane has been isolated by researchers at two universities. The finding, says David J. Miller of the University of Illinois, is a small step in itself but a leap forward in the study of infertility. “We’ve gotten inside the door and past the first step,” he said. “We believe we are looking at a single pathway, but one that may have alternatives along the way.”
Miller’s group of UI researchers and Barry D. Shur of Emory University in Atlanta reported in the February issue of the journal Development that once sperm binds to the protein coat of an egg, a group of G proteins activate. Their subsequent signaling activity opens the gate for sperm to enter.
Shur had reported in 1996 that the protein galactosyl transferase (GalTase) on sperm binds to the protein ZP3 on the zona pellucida – a coat around all mammalian eggs. However, his findings were contradictory: When GalTase was absent, fertility did not stop in mice, but during in-vitro fertilization experiments, a lack of GalTase severely compromised sperms’ ability to penetrate the zona pellucida.
The new research strengthens and advances Shur’s earlier discovery, said Miller, a UI professor of animal science who did postdoctoral research under Shur. This time, researchers focused on ZP3 with a series of molecular experiments that combined components of sperm from mice and egg cells from frogs.
They found that when ZP3 and a “long form” of GalTase lock tightly together, the G proteins, which are present in sperm and eggs, react to release the enzyme vesicles necessary for sperm penetration. Short-form GalTase that contains fewer amino acids does not activate the G proteins when linked with ZP3, researchers found. When they genetically altered an amino acid in the long-form GalTase, G-protein activation stopped and so did the release of vesicles. An additional experiment also showed the necessity of the G proteins; the addition of pertussis toxin, which inactivates them, also blocked the release of the vesicles.
“We now have a better molecular understanding of how sperm binds and gets through the coat around an egg,” Miller said. “We know that G proteins are involved in the signaling process, but there may be another mediating step between GalTase and ZP3 that we don’t know about.”
Miller’s lab is now trying to determine if other receptors on sperm are important. “As more of the questions are answered, we’ll be able to determine if it’s the man or woman who needs to be treated for infertility,” he said. “The knowledge also could lead to better contraceptives, new methods to inhibit pest populations and ways to promote reproduction in farm animals and endangered species.”
The National Science Foundation, National Institutes of Health and the Illinois Agricultural Experiment Station funded the research. Co-authors with Miller and Shur were Miller’s graduate students Xudong Shi, Simin Amindari, Kavitha Paruchuru, Dale Skalla and Heather Burkin.
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