Oocyte meiotic maturation is required for sexual reproduction. Oocyte meiotic maturation is defined by the transition between diakinesis (final stage of meiotic prophase) and metaphase of meiosis I and is accompanied by nuclear envelope breakdown, cortical cytoskeletal rearrangement, and meiotic spindle assembly. In many species, hormones trigger meiotic maturation by regulating CDK/cyclin, MAP kinase, and Gas-regulated protein kinase A pathways. Somatic cells of the gonad also play critical roles in regulating meiotic maturation. Still, there are many gaps in our knowledge of how intercellular signals control meiotic progression and prepare the oocyte for fertilization. Identification of the proximate meiotic signals has proved challenging in mammalian systems and it remains to be determined how these uncharacterized signals are received and processed. Chromosome missegregation in female meiosis I represents the leading cause of miscarriage and Down syndrome and recent work points to hormonal signaling deficits during oogenesis as a significant cause of aneuploidy in humans. Work in our laboratory has established the nematode Caenorhaditis elegans as an important system for studying oocyte meiotic maturation signaling. Our studies demonstrate that C. elegans sperm export the major sperm protein (MSP) by a vesicle budding mechanism to trigger oocyte MAP kinase activation and meiotic maturation. MSP also promotes the contraction of the follicle-like sheath cells that surround oocytes. In the prior funding period, we discovered that an Eph/MSP receptor pathway in the oocyte andantagonistic Gao/i and Gas protein signaling pathways in the sheath cells regulate meiotic maturation in response to MSP. Major goals for the next funding period will be elucidating the biochemistry and cell biology of MSP signaling to address how oocyte and sheath cells coordinately integrate the MSP meiotic maturation signal. To achieve these goals, we will: 1) Elucidate the molecular determinants of the MSP/VAB-1 Eph receptor interaction;2) Define the role of endocytosis in MSP/Eph receptor signaling for oocyte meiotic maturation;3) Determine how the gonadal sheath cells regulate meiotic maturation in parallel to VAB-1. Since developmental signaling mechanisms and the cell cycle machinery are evolutionary conserved, studies in the C. elegans model system will enhance our understanding of human reproduction.
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