The molecular basis of gamete recognition in mice and humans

Successful fertilization heralds the onset of development and requires both gamete recognition and a definitive block to polyspermy. Sperm initially bind and penetrate the extracellular zona pellucida (ZP) that surrounds ovulated eggs, but are unable to bind the zona surrounding preimplantation embryos. The ZP of humans is composed of four (ZP1-4) and that of mouse three (ZP1-3) glycoproteins. Models for gamete recognition developed in mice had proposed that sperm bind to ZP3 glycans. However, phenotypes observed in genetically engineered mice are not consistent with this widely accepted model. More recently, taking advantage of the observation that human sperm do not bind to mouse eggs, human ZP2 was defined as the zona ligand in transgenic mouse models using gain-of-function assays. The sperm-binding site is an N-terminal domain of ZP2 that is cleaved by ovastacin, a metalloendoprotease released from egg cortical granules following fertilization. Proteolysis of this docking site provides a definitive block to polyspermy as sperm bind to uncleaved, but not cleaved ZP2 even after fertilization and cortical granule exocytosis. While progress has been made in defining the ZP ligand, less headway has been made in identifying the cognate sperm receptor. Although a number of sperm receptor candidates have been documented to interact with specific proteins in the ZP in vitro, continued fertility after genetic ablation of the cognate gene indicates that none are essential for gamete recognition. These on-going investigations inform reproductive medicine and suggest new therapies to improve fertility and/or provide contraception, thus expanding reproductive choices for human couples.