Fertility Mystery Solved With Discovery of Protein Key

Infertility can be caused by a number of factors, including (but not limited to) DNA damage, chromosomal aberrations, hormonal conditions, age-related factors, and environmental factors. Some infertility conditions are specific to females, some to males, and some arise because of a combination of conditions in the male and female partners. Approximately 12 steps are involved in thoroughly investigating the cause of infertility in couples. In research published this week in Nature, with Dr. Enrica Bianchi of the Wellcome Trust Sanger Institute in Cambridge, UK as the lead author, scientists have moved closer to solving the mystery of fertility with the discovery of a protein that is key to the interaction of sperm and egg.

Because fertility is such a monumentally important topic, much research has been done on it. An early key to this mystery was discovered in 2005, when researchers found a protein present on the sperm’s surface that recognizes the egg, thereby enabling fusion to form an embryo. They named it “Izumo,” which is Japanese for “marriage shrine.” In today’s study, the research team is reporting the discovery of a cognate protein on the egg’s surface that binds Izumo: they named it Juno, after the Roman fertility goddess. The research study also confirmed that the binding of Izumo to Juno is the first step in the process of egg and sperm fusion, without which fertilization cannot take place. This particular interaction was difficult to pin down, because the binding between Izumo and Juno is low-affinity (i.e. their binding is quite weak). After the egg is fertilized, it rids itself of the remaining Juno protein on its surface within 40 minutes, so as to prevent more sperm from binding: if more than one sperm fused with the egg, the resulting zygote would have too many chromosomes, and would thus be inviable.

In order to perform the experiment, the research team took the already-characterized Izumo protein, and developed an artificial version of it, to see what it bound to on a mouse egg. They used an assay called AVEXIS, which is designed to identify weak and transient interactions between receptors and the ligands they bind to. In this way, they found a folate receptor called Folr4, which they renamed Juno.

To prove that Juno was essential to female fertility, the research team created genetically modified mice that lacked the Juno protein on their eggs. The eggs of these mice did not fuse with sperm, and the mice were infertile. To complete their understanding of the interaction of Izumo and Juno, the researchers genetically modified male mice that lacked Izumo; these mice were then shown to be infertile.

This research is significant because it offers a shortcut through the many steps involved in treatment of infertility. Eggs and sperm of couples experiencing difficulty conceiving can be genetically screened to determine if their Izumo and Juno proteins are structured correctly. If it is established that these proteins are defective, couples can go directly to a procedure called “ICSI” for intracytoplasmic sperm injection, in which a sperm is directly injected into an egg, using an extremely fine needle. Dr. Gavin Wright, who leads the Institute’s Cell Surface Signalling Laboratory, hopes that the discovery of this key protein interaction will solve at least one fertility mystery, and allow improvements to fertility treatments as well as contraceptives.