Professor David Greenstein

Cells of the germline form gametes and establish an unbroken chain between generations. The physical links in this chain, forged by the union of sperm and oocyte at fertilization, are dependent on the faithful execution of meiosis. The conserved process of meiosis ensures that the embryo inherits a proper genome, whereas inheritance of the oocyte cytoplasm and its cellular organelles enables that genome to function. A nearly universal feature of animal development is that oocytes arrest during meiotic prophase, often for a prolonged period (up to 50 years in humans). Defects in female meiosis represent a major cause of human birth defects, miscarriage and infertility. Oocyte growth, which occurs during the period of meiotic arrest, enables oocytes to acquire the cytoplasmic components needed to produce healthy progeny and to gain competence to complete meiosis. Meiotic resumption (also called meiotic maturation) involves the transition to metaphase I, which occurs in response to hormonal signaling and is regulated by soma-germline interactions. Intercellular signaling activates the maturation-promoting factor, which triggers M-phase entry and consists of the Cdk1 catalytic subunit and the cyclin B regulatory subunit. Because the full-grown oocytes of most animals are transcriptionally quiescent, translational regulation is a major control point in the regulation of meiotic maturation. How intercellular signaling regulates protein translation to regulate meiotic maturation and other developmental decisions is not well understood. This research project seeks to fill this knowledge gap by studying how intercellular signaling regulates the activity of conserved translational regulators that coordinately control the oocyte growth process and the meiotic maturation decision. Because ethical issues limit studies in humans, model systems are indispensible.

Over two decades, this research team established the nematode Caenorhabditis elegans as a genetic model for studying the control of meiotic maturation by hormonal signaling. Their studies in C. elegans:

• Reveal how hormonal signaling and soma-germline interactions regulate meiotic maturation
• Define the central molecular machine controlling meiotic arrest and meiotic resumption
• Elucidate the translational control mechanisms by which this machine works
• Unveil deeply conserved regulatory mechanisms controlling the oogenic program
• Delineate how defects in the regulation of meiotic maturation cause infertility and aneuploidy

This research project emphasizes three central questions:

• How a large translational regulatory machine acts as a switch to control meiotic maturation
• How soma-germline interactions regulate oogenesis by the provision of small molecule second messengers via gap junctions
• How the OOC-5/Torsin A AAA+ ATPase facilitates oocyte growth by maintaining the structure and function of the nuclear envelope (mutations in TorsinA in humans cause early onset DYT1 dystonia).

This research will elucidate how intercellular signaling and translational regulation control conserved molecular and cellular events of oocyte growth and meiotic maturation. This basic research will broadly instruct a mechanistic understanding of oogenesis.