In nearly all animals, fully-grown oocytes remain arrested in meiosis for some time until hormones break this arrest by activating poorly understood, complex signal transduction pathways that culminate in the resumption of the cell cycle. This crucial step confers the capacity of the oocyte to respond to sperm. This process of converting the arrested oocyte into a fertilization competent egg is termed maturation. While oocyte maturation is a widely conserved process across all animal species, and some information is known about the hormones that regulate maturation, no oocyte maturation hormone receptor has been identified unambiguously in any species to date, defining a major gap in our understanding of this fundamental event. This proposal outlines a novel strategy designed to identify an oocyte maturation hormone receptor in a simple model system, the starfish oocyte. The starfish was chosen as the model system because the maturation-inducing hormone 1-methyladenine (1-MA) has been identified, and knowledge that the signaling pathway is G-protein linked provides information that will be used to identify the receptor. Distinct homology-based and functional cloning approaches will be used in a tandem effort to identify the cDNA encoding the 1-MA receptor. Identification and characterization of the 1-MA receptor will allow us to then test the widely-held hypothesis that this receptor is a canonical G-protein coupled receptor (GPCR) and eventually, to assess the signaling pathway leading from hormone at the oocyte surface to resumption of meiosis. Further, success using this strategy would provide proof of concept for investigations of the maturation hormone receptors of other species, including mammals. Further, beyond the obvious reproductive biology aspects of the project, oocytes are a good model system in which to understand basic cell signaling events. Finally, cancers result from an abnormal and unregulated growth of cells, which often is normally regulated by signaling cascades involving GPCRs. Therefore, the oocyte maturation studies proposed here potentially will provide new insights for the mechanisms of cell growth regulation and perhaps lead to a deeper understanding of how cancer develops.
