Reproductive assist

Finding sheds light on infertility puzzle,
could improve in vitro fertilization

We don’t know if a sperm actually experiences joy when it finally finds the egg, but it does wiggle excitedly. Patricia A. Martin–DeLeon, a reproductive biologist at the University of Delaware, has witnessed this behavior many times in her studies of fertility in mice, the closest genetic model to humans (and with a much faster reproductive cycle).

In a recent issue of the Journal of Biological Chemistry, Martin–DeLeon and her team revealed for the first time what happens next in the fertilization process. They said the finding could one day help couples struggling with infertility.

Once an egg exits an ovary and enters the fallopian tube, the hairlike cilia that line this tiny tube sweep the egg toward the uterus. While in the tube, the egg either meets the sperm and gets fertilized, which must happen within a 12- to 24-hour window, or dissolves.

In 2013, Martin–DeLeon and her team reported the discovery of special vesicles in fallopian tubes. They named these cargo-filled sacs oviductosomes. Inside these vesicles, they found a calcium-clearance pump, plasma membrane Ca2+-ATPase 4, among other things.

In their recent JBC paper, Martin–DeLeon and her team report that oviductosomes help the sperm get ready for its all-important drive into the end zone. The tiny, cargo-filled sacs attach to the sperm like decorations on a Christmas tree before the sperm fuses with the egg. Once these sacs are in place, they transfer proteins, including the calcium-clearance pump, to the sperm.

“This calcium pump is required by the sperm just prior to fertilization, as well as in the early embryo,” Martin–DeLeon says. “The sperm pumps out calcium and takes in hydrogen ions, which seems to give it that last push into the egg and also is critical to starting the zygote’s life.”

Martin–DeLeon and her team labeled oviductosomes from a female mouse with a fluorescent dye and incubated them together with the sperm. Within an hour, the oviductosomes fused to the sperm’s surface. After two to three hours, the oviductosomes continued to accumulate, primarily on the sperm’s head and the midpiece of its tail. Integrins, membrane receptors on both the sperm and the oviductosomes, helped to facilitate their bonding, along with fusion stalks on the sperm’s surface.

“Discovery of these oviductosomes provides us with a window into the cargo being delivered by the female to the sperm,” Martin–DeLeon says. “We’ve shown that these oviductosomes are carrying critical molecules that include not only proteins, but also nucleic acids such as RNA and also lipids. That gives us hope they can be used as vehicles for improving fertility and the chances of producing healthy embryos and offspring.”

Martin–DeLeon and her team now are analyzing the protein-rich cargo to find out exactly what gives the sperm what it needs for its last push to penetrate the egg — always head first, tail out — to fertilize it. “We may identify proteins required to improve the efficiency of (in vitro fertilization), and improve the outcome and health of the offspring,” she said. “It’s really another step in the direction of personalized medicine, since individuals carrying mutations of one of a variety of genes account for the largest group of infertile couples.” 

Tracey Bryant Tracey Bryant is director of research communications at the University of Delaware.