The role of sperm inner acrosomal membrane proteins in acrosomal biogenesis and fertilization

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Fertilization is the cornerstone of development where the two differentiated cells, sperm and egg set the stage for embryogenesis and beyond, for which competency of the gametes is essential. Yet only rudimentary knowledge is available on the molecules and mechanisms involved in sperm-egg interactions leading to zygotic development. This is underscored in consideration that 30-50 % of male-factor infertility cases have no known cause. Our strategy in gaining an understanding of these mechanisms is to isolate and molecularly dissect sperm compartments (e.g., acrosome and perinuclear theca) that are involved in the fertilization process. The identities of the proteins provides clues to the compartment's significance and allows us to design specific probes (e.g., antibodies, and wild type and mutant recombinants and competitive inhibitors) to test the predicted functions and mechanisms of these proteins during fertilization and/or spermiogenesis. Utilizing this approach, under the mandate of the NSERC Discovery Grant, my student trainees and I have investigated the function of the inner acrosomal membrane (IAM). This sperm component plays a critical role during fertilization as it is exposed by the acrosome-reaction and then binds the sperm firmly to the zona pellucida (ZP) of the egg, a compulsory step for subsequent IAM-directed sperm penetration of this extracellular matrix. Before our study the proteins of the IAM were unexplored. We have identified and characterized the following IAM proteins: IAM38, binding receptor to ZP; MMP2, potential ZP penetrating enzyme; proacrosin, potential MMP activating enzyme; SPACA1, trans-membrane protein which potentially organizes and attaches these proteins to the IAM; SubH2Bv, KAPa and KAPß which form a complex and potentially direct the acrosomic vesicle to the nucleus during spermiogenesis. The present proposal intends to validate the potential functions of these proteins and elucidate their mechanisms of action. The knowledge gained would unquestionably lead to a better understanding of the origins of sperm infertility defects and their diagnosis. It could also serve to improve application of Assisted Reproductive Technologies and to design a contraceptive.