On the molecular mechanisms controlling oocyte meiotic maturation in Caenorhabditis elegans

Abstract

A conserved biological feature of sexual reproduction in animals is that oocytes arrest in meiotic prophase and resume meiosis in response to extra-ovarian signals. While meiotic maturation signals activate highly conserved pathways (e.g. MAP kinase and CDK/cyclin B), the receptor signaling mechanisms involved are less well defined. In C. elegans, sperm trigger meiotic resumption using the Major Sperm Protein (MSP) signal. MSP signaling involves two parallel genetic pathways, defined by vab-1, which encodes an MSP/Eph receptor protein-tyrosine kinase, and ceh-18, which encodes a POU-homeoprotein expressed in gonadal sheath cells. vab-1 and ceh-18 negatively regulate MAP kinase (MAPK) activation, and MSP relieves this inhibition to promote meiotic maturation. MSP directly binds VAB-1 on oocytes, but as vab-1 null mutants respond normally to MSP, signaling must also involve the function of unidentified receptors. ceh-18 functions in the gonadal sheath cells, indicating that sheath¬-oocyte communication may be important in maintaining meiotic arrest. Thus, additional components of the vab-1 and ceh-18 pathways function to negatively regulate MAPK activation and meiotic maturation in the absence of MSP. Using a genome-wide RNAi screen in a female-sterile genetic background, I identified seventeen conserved genes that maintain meiotic arrest in the absence of the MSP signal. Four conserved proteins, including a disabled protein (DAB-1), a vav family GEF (VAV-1), a protein kinase C (PKC-1), and a STAM homolog (PQN-19), function with the VAB-1 Eph/MSP receptor in oocytes. I show that antagonistic Gás and Gáo/i signaling pathways function in the soma to regulate meiotic maturation in parallel to the VAB-1 pathway. Gás activity is necessary and sufficient to promote meiotic maturation, which it does in part by antagonizing inhibitory sheath/oocyte gap-junctional communication. Further evidence shows that MSP signaling reorganizes oocyte microtubules through a signaling network involving antagonistic Gás and Gáo/i pathways and gap-junctional communication with somatic cells of the gonad. I propose that MSP-dependent microtubule reorganization promotes meiotic spindle assembly by facilitating the search and capture of microtubules by meiotic chromatin following NEBD. My findings show that oocyte Eph receptor and somatic cell G protein signaling pathways control meiotic diapause in C. elegans, highlighting contrasts and parallels between MSP signaling in C. elegans and luteinizing hormone signaling in mammals.