GaMe · Mechanism of vertebrate sperm-egg recognition and fusion

The life of every sexually reproducing being can be traced back to a singular event: the fusion of sperm and egg. Gamete fusion is perhaps the most critical step in the process of fertilization. However, the mechanisms underlying vertebrate sperm-egg fusion and the events that precede it (sperm-egg recognition) are largely unknown. Uncovering the molecular machinery and biophysical mechanisms mediating sperm-egg recognition and membrane fusion in vertebrates is therefore one of the biggest challenges in fertilization research. In this project we aim to uncover the mechanistic principles of vertebrate fertilization by exploiting the unique advantages of zebrafish as a vertebrate model in combination with in vitro reconstitution assays. We will focus on two main questions:1)What is the molecular mechanism of sperm-egg recognition?2)What are the molecular and biophysical principles underlying sperm-egg fusion?To identify new essential components of the sperm-egg recognition and fusion machineries, we will develop candidate and unbiased screening approaches. We will combine functional studies in vivo, using phenotypic, genetic, biochemical, and advanced high-resolution imaging approaches, with mechanistic studies in vitro, using structural and reconstitution assays, to rigorously determine requirement and sufficiency, causal relationships, spatiotemporal dynamics and mechanisms. Our recently discovered fertility factors Bouncer (sperm-egg recognition) and Dcst1/2 (sperm-egg fusion) provide precise entry points for screens and for functional and mechanistic studies.Overall, our goal is to mechanistically understand how sperm and egg recognize and bind to each other, and how their membranes subsequently fuse. The insights gained will form the basis for our ultimate vision, to reconstitute a functional ‘fertilization interface’ in vitro, and by these means understand one of the most fundamental processes of life.