Phosphoinositide signaling and sperm fertility

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DESCRIPTION (provided by applicant): Mammalian sperm are stored in the male reproductive tract in an immotile and infertile state. The ability to reach the site of fertilization and to interact with eggs successfully is only developed during incubation within the female reproductive tract. The molecular alterations in sperm that account for this functional maturation are, collectively, known as capacitation. These processes are essential for reproduction. As such, the physiological regulators of capacitation may provide novel targets for contraceptive intervention. Polyphosphorylated phosphoinositides in the sperm membrane mediate key steps in capacitation and sperm-egg interaction. However, little is known about the lipid kinases and phosphatases that regulate the levels of these phosphoinositides. Here, we focus on the 3'-phosphoinositide phosphatase, Tpte. As will be discussed, Tpte transcripts are detected only in spermatogenic cells and the anticipated enzymatic activity suggests a role in capacitation. In addition, preliminary data is presented showing that cauda epididymal mouse sperm contain enzymatically-active Tpte protein in the anterior head and in the flagellum. However, we have no direct information regarding the role of this protein in sperm due to a lack of reagents. In this exploratory study we will generate a mouse line in which the Tpte locus is mutated and lacking phosphatase activity, and examine the reproductive phenotype of these mice. In addition we will begin an analysis of the catalytic activity of Tpte phosphatase activity. This exploratory study represents the first stage of a long-term effort to determine the role of Tpte, as well as other phosphoinositide kinases and phosphatases, in sperm function and reproduction. PUBLIC HEALTH RELEVANCE: This project focuses on the control of sperm fertility. As such, it directly relates to two issues of health relevance. First, episodes of infertility affect 10-15% of couples in the US and this work may lead to new treatments for this condition. Second, population is now estimated to exceed 6,700 million world-wide. This project examines a sperm-specific lipid phosphatase that would provide a novel target for contraceptive intervention. The experiments carried out here will determine the role of this phosphatase in sperm fertility and begin characterization of phosphatase activity.