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Sperm-Egg Interactions in Mammalian Fertilization

Cell-cell interactions are fundamental to the survival of a multi-cellular organism. Control and diagnosis of normal and abnormal cell-cell interactions is important in all areas of human health ranging from embryonic development and immune function to uncontrolled tumor growth in cancer. For example, understanding the molecular mechanisms of sperm-egg recognition is required for treating infertility and developing new, non-hormonal methods of contraception.

We investigated the role of beta1 integrin in mammalian fertilization and the mode of inhibition of fertilinbeta-derived polymers. We determined that polymers displaying the Glu-Cys-Asp peptide from the fertilinbeta disintegrin domain mediate inhibition of mammalian fertilization through a beta1 integrin receptor on the egg surface. Inhibition of fertilization is a consequence of competition with sperm binding to the cell surface, not activation of an egg-signaling pathway. Most importantly, the presence of the beta1 integrin on the egg surface increases the rate of sperm attachment, but does not alter the total number of sperm that can attach or fuse to the egg. We conclude that the presence of beta1 integrin enhances the initial adhesion of sperm to the egg plasma membrane and that subsequent attachment and fusion are mediated by additional egg and sperm proteins present in the beta1 integrin complex. Therefore, the mechanisms by which sperm fertilize wild-type and beta1 knockout eggs are different. Our work highlighted the importance of using kinetics in the fertilization assays to more fully assess the phenotype of knockout eggs. Currently in the laboratory, we are using proteomic methods with whole-animal isotope labeling to investigate additional differences between wild-type and knockout eggs.

An important step in fertilization is binding of the sperm to the outer glycoprotein coat of the egg, the zona pellucida (ZP). The sperm must digest and traverse the ZP in order to reach the egg plasma membrane before fusion and fertilization can occur. The sperm acrosome reaction, proposed to initiate by binding to the ZP, results in release of digestive enzymes and matrix proteins from the sperm acrosomal vesicle. Oligosaccharides isolated from the ZP do not activate the acrosome reaction; they must be presented in a multivalent fashion. Many candidate ligands and receptors have been investigated; however, currently available biochemical and genetic methods have not definitively identified the ZP saccharides and sperm receptors that engage and lead to acrosome reaction. Defined molecular systems to unravel these complex cell-cell interactions are needed. Identification of the sugar moieties required for acrosome reaction and their receptors is necessary for controlling normal sperm function and diagnosing causes of abnormal sperm function.

We are developing libraries of neoglycopolymers to screen for initiation of the sperm acrosome reaction. We can control functional group density, backbone flexibility, and functional group variety in the polymer synthesis to provide a powerful, molecular approach to further investigate the acrosome reaction, and cell-cell interactions, in general. This work builds on the polymer synthesis work developed in our lab.

 

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