New players in the fertilization may help to address infertility

New players in the fertilization may help to address infertility

An unexpected discovery about fertilization reveals new insights on how sperm and egg fuse and could have major implications for couples battling infertility - and may lead to a future male contraceptive. The finding has the potential both to boost the success rate of in-vitro fertilization and reduce its cost.

The finding recasts the role of the egg in the fertilization process. The old notion of the egg as a passive partner for sperm entry is out. Instead, the researchers found, there are molecular players on the surface of the egg that bind with a corresponding substance on the sperm to facilitate the fusion of the two. "High school biology taught us a very sperm-centric version of fertilization," said the researcher. "And now it's very clear that it is a dynamic process where both the sperm and egg are equally and actively involved in the ultimate biological goal of achieving fertilization."

The researchers started collaborating few years back on how immature sperm go through developmental stages in the testes. During their studies, they noticed something unusual. Some immature sperm that appeared to be dying weren't dying at all - they were alive and healthy. These sperm had a molecular marker on their surface suggestive of a dying cell, and this marker grew stronger as the sperm matured. "This initially made no sense," the author said. "We had to do a lot of experiments to show that, indeed, these were live, motile sperm."

It turned out that this marker on the sperm that often tells the body to remove dying cells is used differently and in an important way during fertilization. This marker, phosphatidylserine (PS), is normally held inside cells until they die, but it is also exposed, quite deliberately, on healthy, live sperm.

The egg, meanwhile, expresses protein partners that specifically and actively engage the PS on the sperm. This PS-based recognition, along with other interactions, promotes sperm-egg fusion.
In the oocyte, phosphatidylserine recognition receptors BAI1, CD36, Tim-4, and Mer-TK contribute to fertilization. Further, oocytes lacking the cytoplasmic ELMO1, or functional disruption of RAC1 (both of which signal downstream of BAI1/BAI3), also affect sperm entry into oocytes. Intriguingly, mammalian sperm could fuse with skeletal myoblasts, requiring PtdSer on sperm and BAI1/3, ELMO2, RAC1 in myoblasts.Masking the PS on the sperm, or preventing the receptors on egg from recognizing the sperm, block fertilization quite efficiently.

That has several intriguing implications. First, for couples struggling with infertility, doctors one day might try to enhance the exposure of PS on the sperm to promote the chance of conception. They also could examine a man's sperm before in-vitro fertilization to select sperm that are most likely to result in pregnancy. This could help prevent the need for multiple attempts and reduce the cost couples must bear.

"When men go in for infertility tests, they do a basic semen analysis, and the current analysis primarily looks at the number of sperm, can it swim and how does it look," the author said. "It doesn't provide much of an idea of the sperm's fitness to fertilize." As part of this work, the research groups have also designed a new test to determine the fertilization fitness of the sperm based on exposure of PS.

Second, the researchers believe that finding a way to mask phosphatidylserine on the sperm head could be a potential form of contraception. "It is a very likely possibility," the author said. "We blocked phosphatidylserine by three or four different ways [in lab dishes], and we are pleasantly surprised how well it blocks sperm-egg fusion."