Control of Oocyte Maturation in C. elegans

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Oocyte maturation and ovulation are essential biological processes required for sexual reproduction. During oocyte maturation, oocytes enter meiotic M phase from prophase due to activation of the Cdc2/CyclinB protein kinase, maturation- promoting factor (MPF). In many species, hormones trigger signal transduction cascades that promote oocyte maturation and ovulation, but a major outstanding question concerns the detailed molecular mechanisms involved. A failure to correctly regulate this critical meiotic cell cycle transition can result in infertility, miscarriage, or Down's syndrome. The signal that promotes oocyte maturation in mammals is not known, and a receptor for a maturation-inducing substance has not been identified in any organism. To complement studies in vertebrates, we are using the nematode Caenorhaditis elegans as a model for studying the control of oocyte maturation and ovulation by intercellular signaling. Our studies demonstrate that a sperm cytoskeletal protein, the major sperm protein (MSP), is a bipartite signal that promotes oocyte maturation and gonadal sheath cell contraction in C. elegans. We have shown that MSP binds to oocytes and activates the conserved MAP kinase cascade. Our results indicate that MSP binding to oocytes requires the function of the VAB-1 Eph receptor tyrosine kinase and a highly conserved Hem family protein, SIM-2. MSP signaling results in diverse cellular responses including M-phase entry, cortical cytoskeletal rearrangement, meiotic spindle assembly, and gonadal sheath cell contraction. These responses are required for ovulation, fertilization, and completion of the meiotic divisions. To elucidate the mechanisms by which extracellular signals promote oocyte maturation and ovulation, we are taking a multipronged approach by studying the MSP signal, candidate receptors, and potential downstream signaling mechanisms. This proposal aims to: 1) define the conserved MSP domains that signal to oocytes and sheath cells; 2) determine whether MSP binds to the VAB-1 (Eph) receptor and the SIM-2 HEM-2-related protein on oocytes to promote maturation; and 3) conduct a genetic analysis of the MSP signaling pathway.