Apical constriction is a cell shape change that drives fundamental events of morphogenesis, including gastrulation in many animals and neural tube formation in vertebrates. An understanding of the mechanisms by which cells shrink their apical domains will provide insights into how animals are shaped, and it will contribute to a basic foundation for the diagnosis and prevention of human neural tube closure defects. The long-term goal of this project is to understand how forces are produced and transmitted with spatiotemporal precision to shape cells and tissues in developing organisms. C. elegans gastrulation serves as a model for revealing mechanisms of apical constriction-dependent morphogenesis. Gastrulation in C. elegans begins with two endodermal precursor cells undergoing apical constriction and moving from the embryo's surface to the interior, at the 26- to 28-cell stage of embryonic development. Using C. elegans makes it possible to combine in a single system many tools that are valuable in other model systems, including tools used primarily in cultured cell systems in which some complex developmental phenomena cannot be studied. These tools include genetic screens and genetic manipulations, quantitative imaging of subcellular dynamics in two large, predictably positioned and optically clear cells, probing of forces by laser microsurgery, and some newly developed tools.
The specific aims of this project are to dissect precise mechanisms by which apical constriction is triggered by connecting the edges of the cells' apical surfaces to pre-existing actomyosin contractions, to determine the role of extracellular matrix in apical constriction by studying an extracellular matrix component that contributes to C. elegans gastrulation, and to identify and study new proteins that contribute to the mechanisms studied above. The work has the potential to establish new and unexpected mechanisms for a developmental cell shape change that is important to morphogenesis in diverse animals and with potential relevance to human neural tube defects.
Neural tube defects comprise the second leading class of birth defects, occurring annually in approximately 300,000 newborns worldwide. This proposal seeks to understand apical constriction, a change in cell shape that contributes to successful neural tube closure, using the roundworm C. elegans as a simple model for efficient investigation of cellular and molecular mechanisms. The long-term goal of the work is to understand fundamental mechanisms that can lay the foundation for future diagnosis and prevention of neural tube defects.
Showing the most recent 10 out of 43 publications
