Investigating the mechanisms that regulate apical constriction during C. elegans gastrulation.

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

? DESCRIPTION (provided by applicant): Apical constriction is a commonly used mechanism to change a cell's shape and initiate morphogenesis in broad range of animal systems, including the vertebrate neural tube. Apical constriction occurs as a result of actomyosin contractions at the apical surface, which serves to shrink the exterior face of the cell and squeeze it into the interior of the embryo. Gaining an understanding of the mechanisms that control apical constriction can answer fundamental questions about processes that shape embryos during development and build a knowledgebase for diagnosing and preventing human neural tube closure defects, which currently are one of the most common and serious human birth defects. The long-term goal of the proposed project is to understand the mechanisms used by cells and tissues during development to spatially and temporally regulate the forces that generate shape changes. The proposed project will use Caenorhabditis elegans gastrulation as a model for studying the mechanisms of apical constriction. Gastrulation in C. elegans involves two endodermal cells that shrink their apical surfaces and move from the embryo's surface to the interior at the 26-28 cell stage. Previous work in this system has demonstrated that actomyosin contractions begin before the cells' surfaces begin to shrink. After several minutes, the edges of the cells begin to move along with actomyosin contractions. This surprising result suggests that the link between the actomyosin and cell-cell junctions is either absent, or inhibited, prior to ths point. The objective of this proposal is to understand the mechanisms through which cells change shape during development, in vivo. The experiments proposed within take full advantage of the strengths of the model system, which allows for easy genome editing through CRISPR/Cas9, biochemical methods, genetic screens, and represents a simplified developmental context in which to study these complex mechanisms. The aims described within propose to (1) validate a list of candidate proteins in order to determine if any contribute to a physical link that couples cell-cell junctions to pre-existing actomyosin contractions, resulting i apical constriction, (2) identify the role of a transmembrane protein that is expressed at the star of apical constriction and localizes to the interface between constricting cells. Successful completion of these aims will lead to an understanding of the mechanisms that regulate apical constriction, an important developmental process. These experiments could identify new mechanisms through which cytoskeletal links are regulated and discover new proteins that could be involved with morphogenesis in diverse animal systems, including neural tube closure in humans.