Cell Surface Receptor Recognition and Membrane Fusion in Mammalian Fertilization

Fertilization is an essential biological process that involves cell surface recognition, adhesion, and fusion of haploid sperm and egg to form a new, genetically distinct diploid organism. Surprisingly little is known about how plasma membranes interact and fuse, largely due to the limited availability of mammalian gametes and the technical challenges of capturing transient extracellular interactions. While the gamete membrane fusion machinery remains elusive, it is known that a human immunoglobulin superfamily protein, Izumo1, localizes to the equatorial segment of spermatozoon, where it interacts with an oocyte ligand, Juno, before gamete fusion takes place. To date, Izumo1-Juno is the only essential receptor-ligand pair identified in the pathway. Recent genetic studies in mice have identified additional sperm surface proteins essential for male fertility, but their interactions and regulation have not been defined. To close these major gaps, I have designed a research program around the central hypothesis that gamete surface proteins orchestrate their structural rearrangements and membrane remodeling, leading to gamete fusion. I will test my hypothesis by (1) determining the assembly mechanisms of sperm fertilization protein IZUMO1, (2) characterizing the roles of sperm fertilization proteins in membrane adhesion and fusion, and (3) identifying additional receptor-ligand interactions essential for fertilization. My multidisciplinary approach leverages high-resolution structural analyses to interrogate the functional organization of known essential gamete surface proteins, and harnesses high-throughput forward genetic screens to explore the interacting networks of additional emerging molecules. I have extensive training in genetics, cell biology, membrane biochemistry, protein engineering and structural biology. At Yale, my research laboartory aims to understand the mammalian sperm-egg fusion process at the levels of cell biology, mechanistic biochemistry, and structural biology. Crucially, understanding these processes will elucidate mechanisms of cell-cell adhesion and fusion and reveal essential factors for human fertility and reproductive health.