Genetic control of C. elegans gastrulation

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DESCRIPTION (provided by applicant): Gastrulation is a critical time in early development when cells organize themselves spatially within the embryo according to what they will become. The cell movements of gastrulation must be intimately controlled to prevent catastrophic defects in organization of the embryo that can cause birth defects or miscarriage, yet we know little about how gastrulation control is effected. In particular, although it is clear from work in several model species that cell fate specification genes can direct gastrulation movements, the identities and functions of the downstream effectors controlling gastrulation are largely unknown. The specific goal of this proposal is to identify and characterize genes that function downstream of cell fate specification genes to control gastrulation movements. Our long-term goal is to have a complete picture of how cell fate specification genes, gastrulation control genes, and basic cytoskeletal and cell polarity proteins function together to induce, effect, and coordinate gastrulation movements. In this proposal, we take advantage of the optical clarity and genetic manipulability of the C. elegans embryo to identify and characterize gastrulation control genes. Because conserved cellular mechanisms appear to operate during gastrulation, our studies take advantage of the strengths of C. elegans to uniquely complement studies in other vertebrate and invertebrate model organisms. Gastrulation of C. elegans endodermal cells is triggered by the transcription factors END-1 and END-3, which are also required for endoderm specification. However, downstream effectors of END-1 and END-3 important for gastrulation are unknown. In preliminary studies, we have performed microarray experiments to identify a set of previously unknown END effector genes. Here, we propose genetic and cell biological experiments to identify and characterize those important for gastrulation, and additional experiments to identify the actomyosin regulatory proteins that likely interface with the END effectors to control gastrulation. Finally, we propose experiments to determine whether Wnt signaling has a direct role in promoting gastrulation, as recently proposed, or whether Wnt signaling contributes to gastrulation indirectly through its known role in specifying endoderm. These experiments will provide the first foundation for understanding the genetic logic of C. elegans gastrulation. Because many of the cell biological events of gastrulation are conserved, we anticipate that our findings - and future studies that arise from them - will lead to a better understanding of this critical yet mysterious stage of human embryonic development. PUBLIC HEALTH RELEVANCE: Gastrulation is a critical stage in human embryonic development when the basic body plan is established through regulated cell movements. The goal of this proposal is to identify the genes important for gastrulation cell movements and learn how these genes function. These studies will help in understanding the cause of human birth defects and miscarriages that result from abnormal gastrulation.