Nature 508, 483–487 (2014)

Credit: NATURE

During mammalian fertilization, sperm are believed undergo the acrosome reaction when coming into contact with the extracellular matrix—the zona pellucida—of egg cells. This exposes the Izumo1 receptor on sperm, which is essential for recognition of the egg. Despite knowing the identity of this sperm component of the interaction, the receptor on eggs that recognizes Izumo1 has been difficult to identify. One clue about the receptor is that removing glycophosphatidylinositol (GPI) linkages from cell surface proteins renders eggs incapable of being fertilized. Bianchi et al. now used an Izumo1 ectodomain probe and a mouse oocyte cDNA library to identify Folr4, a member of the folate receptor family, as the egg receptor for Izumo1. Folr4, which the authors renamed 'Juno' after the Roman goddess of marriage, is GPI anchored and does not bind folate. Antibodies against Juno blocked binding of the Izumo1 probe to oocytes and blocked in vitro fertilization (IVF). SPR showed the Izumo1-Juno interaction to be highly transient. Female but not male Juno-deficient mice were infertile despite ovulating morphologically normal eggs that could be penetrated by sperm. Subsequent IVF experiments and experiments where nonfusing cells were separately transfected with the receptors suggested that the Izumo1-Juno interaction is necessary for adhesion, but not fusion, between sperm and egg. Finally, the authors found that cell-surface Juno was rapidly lost into extracellular vesicles after fertilization, providing a mechanism for the membrane block to polyspermy, the ability of eggs to regulate the fusion with one—and only one—sperm.