The long-term objectives of the research plan are to elucidate the mechanisms by which mammalian sperm process extracellular messages into intracellular second messengers which modulate sperm function. Fertilization represents an elegant model of intercellular communication and cell-cell interaction. In all mammals, initial sperm-egg interaction occurs at the zona pellucida (ZP), an extracellular matrix synthesized by the growing oocyte. In many mammals, binding of acrosome-intact sperm to the ZP is species-specific and is an absolute prerequisite for sperm acrosomal exocytosis, an event which is critical for sperm penetration of the ZP, sperm binding to the egg plasma membrane, and membrane fusion events leading to egg activation and the initiation of preimplantation development. ZP-mediated acrosomal exocytosis has similarities to receptor-mediated secretory processes in somatic cells. In the mouse, several criteria support this idea: 1) the ZP glycoprotein, ZP3, is the physiologically- relevant ligand that mediates both sperm binding to the ZP and induces acrosomal exocytosis, 2) ZP3 binding proteins are present on the plasma membrane overlying the acrosome, suggesting that sperm possess complementary ZP3 receptors, 3) sperm contain heterotrimeric guanine nucleotide binding regulatory proteins (G proteins), which are signal transducing proteins that play a regulatory role in ZP3-mediated acrosomal exocytosis, and 4) ZP/ZP3 cause changes in sperm pHi and cAMP concentrations, suggesting that ionic/second messenger changes occur in response to ZP3-receptor interactions. this proposal addresses specific questions related to the dynamics of ZP/ZP3-sperm membrane-G protein interaction that effect signal transduction leading to acrosomal exocytosis. Cell biological and biochemical approaches will be used to, 1) characterize ZP/ZP3-sperm membrane dynamics regulating G protein-mediated signal transduction, 2) identify and characterize the biochemical components that form the functional signal transduction complex which forms in response to ZP/ZP3-sperm membrane interaction, and 3) characterize the mechanism by which ZP/ZP3 regulates the sperm adenylyl cyclase. These studies should contribute to a greater understanding of the biochemistry of mammalian fertilization and will provide a working model with which to design rational therapies for the promotion or intervention of sperm-egg interaction.

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University of Pennsylvania
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