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Fertilization occurs when sperm and egg recognize each other and fuse to form a new, genetically distinct organism. The molecular basis of sperm-egg recognition is unknown, but is likely to require interactions between receptor proteins displayed on their surface. Izumo1 is an essential sperm cell-surface protein, but its receptor on the egg has not been described. Here we identify folate receptor 4 (Folr4) as the receptor for Izumo1 on the mouse egg, and propose to rename it Juno. We show that the Izumo1-Juno interaction is conserved within several mammalian species, including humans. Female mice lacking Juno are infertile and Juno-deficient eggs do not fuse with normal sperm. Rapid shedding of Juno from the oolemma after fertilization suggests a mechanism for the membrane block to polyspermy, ensuring eggs normally fuse with just a single sperm. Our discovery of an essential receptor pair at the nexus of conception provides opportunities for the rational development of new fertility treatments and contraceptives.
Fertilization is the culminating event in sexual reproduction and requires the fusion of haploid sperm and egg to create a new, genetically distinct, diploid organism. Sperm acquire the ability to fertilize the eggwithin the female reproductive tract by exposing previously concealed receptor proteins onto their surface following the acrosome reaction1. Once fertilized, both the oolemma and zona pellucida are biochemically altered, making the egg unreceptive to additional sperm and thereby reducing the chances of creating nonviable polyploid embryos2. Several receptor proteins have been implicated in the recognition and/or fusion process3, but just two significantly affect fertility in vivo: Izumo1 on sperm4, and CD9on eggs5-7. Izumo1 (named after a Japanese marriage shrine) is redistributed to the surface of capacitated sperm8, andIzumo1-deficientmale- but not female-mice are infertile because sperm lacking Izumo1 cannot fuse with eggs4. Recombinant Izumo1 binds both wild-type and CD9- deficient eggs, suggesting that Izumo1 interacts with an egg receptor other than CD99. Glycophosphatidylinositol (GPI)-anchored receptors on the egg are essential for fertilization because removing them either enzymatically10 or genetically11 renders eggs infertile. Despite these advances, the molecular basis of gamete recognition in mammals is unknown; in part, this is due to the scarcity of eggs, the challenges in solubilising membrane-embedded proteins, and the often transient nature of their extracellular interactions12. To address these challenges, we...