The oocytes of most sexually reproducing animals arrest in diplotene or diakinesis of meiotic prophase I. Human oocytes enter meiosis in the embryo and maintain prophase arrest for decades. Oocyte growth occurs during the period of prophase I arrest, which enables them to acquire competence to complete meiosis and to produce healthy progeny. Hormonal signaling and soma-germline interactions regulate meiotic resumption (oocyte meiotic maturation). Meiotic maturation is defined by the transition to metaphase I, and its hallmarks are nuclear envelope breakdown, rearrangement of the cortical cytoskeleton, and meiotic spindle assembly. A failure of oocytes to undergo meiotic maturation results in sterility, whereas improper execution of the meiotic divisions causes aneuploidy. The timing of meiotic maturation is crucial. If oocytes undergo meiotic maturation prematurely, their capacity to produce healthy offspring is diminished. The molecular mechanisms that control and coordinate oocyte growth and meiotic maturation are incompletely understood. This application seeks to fill this knowledge gap by studying conserved translational regulators that coordinate and control the meiotic maturation decision and the growth process. We address mechanistic questions about how intercellular signaling and translational regulation control meiotic resumption. Defects in oogenesis represent a major cause of human birth defects, miscarriage and infertility. Ethical and technical issues limit the mechanistic depth of human studies. Oocyte meiotic maturation is an ancient reproductive process and many of its defining features are deeply conserved in evolution. Model systems are thus indispensable to the analysis of female meiosis. Because the full-grown oocytes of most animals are transcriptionally quiescent, translational regulation is a major control point. Our understanding of how signaling controls translation to regulate oocyte growth and meiotic maturation is incomplete. We developed C. elegans as a genetic model for studying the control of meiotic maturation by hormonal signaling. Our work shows that C. elegans and mammals share remarkable similarities in the hormonal control of meiotic maturation.
Our Aims are 1) Elucidate how translational regulators control oocyte growth and meiotic maturation; 2) Define how the SACY-1 DEAD-box RNA helicase regulates oocyte meiotic maturation; and 3) Determine how soma-germline gap junctions regulate meiotic maturation. The proposed experiments will provide mechanistic insights into how intercellular signaling and translational regulation control key cellular events of oocyte meiotic maturation. This basic research in a genetic model system will generate fundamental knowledge relevant for understanding human reproduction.
Defects in oocyte growth and the completion of meiosis (meiotic maturation) represent a major cause of human birth defects, miscarriage and infertility. Because ethical and technical issues limit the mechanistic depth of data obtained from human studies, model systems are invaluable for understanding the cellular events of female meiosis and their control. This application will delineate essential conserved mechanisms by which intercellular signaling and translational regulation coordinate and control oocyte growth and meiotic maturation in the nematode Caenorhabditis elegans.
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