The C. elegans Germline: A Test Tube for Cell and Developmental Biology

SUMMARY/ABSTRACT Overview: Reproduction relies on a complex series of cell fate decisions, cell cycle transitions, and differentiation events, which coordinate the formation and function of gametes with the process of meiosis. A century of research using many experimental organisms, including the nematode Caenorhabditis elegans, defined key intercellular signals regulating germline development, delineated central players in meiosis, and revealed the importance of post-transcriptional gene regulatory mechanisms. Yet, important mechanistic questions remain about how intercellular communication integrates the underlying molecular mechanisms into a coherent germline developmental program. This research proposal addresses several central questions: •How do soma-germline gap junctions orchestrate germline development, coordinate germline developmental subroutines, and integrate nutritional signals to optimize reproduction? •How do intercellular signals and gametic interactions regulate protein translation to enable fertilization and ensure the vitality of the embryo? •Can we exploit the dynamic nature of germline development in which germ cell nuclei move within the gonadal tube to provide broad insights into the cell biology of diseases affecting the nuclear envelope? Goals: The chief goal of our work is to delineate the regulatory networks governing conserved and essential steps in germline development. Our focus will be on three areas: (1) The role of gap junctions in controlling soma-germline interactions; (2) The regulation of protein translation by intercellular signaling during oocyte meiotic maturation and the oocyte-to-embryo transition; and (3) Studies in the C. elegans germline system that provide insights into the cell biology of a class of human diseases affecting the nuclear envelope. In pursuing these goals, we will fill three key gaps in understanding: (i) the nature of the active biomolecules that transit through gap junctions to mediate their many essential reproductive functions; (ii) the function and regulation of a large translational regulatory machine that lies at the heart of the oocyte meiotic maturation decision and the oocyte-to-embryo transition; and (iii) the involvement of nuclear mechanotransduction and endogenous mechanical forces in the origin of diseases affecting the nuclear envelope. Vision: Using the powerful combination of genetic and modern molecular technologies available in C. elegans, we will advance our understanding of germline development, germline stem cell behavior, and oogenesis. In the course of these investigations, we will discover new molecular principles vital to human health and inform the development of novel therapeutic strategies to treat disease. This fundamental research in a genetic model system will generate foundational knowledge for understanding reproduction and the origin of birth defects.