Novel regulators of apical constriction

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DESCRIPTION (provided by applicant): This proposal concerns molecular mechanisms leading to the formation of apically constricted cells in the vertebrate embryo. Apical constrictio is a process, during which the apical surface of a cell is reduced causing the cell to take on a wedged shape. These coordinated cell shape changes drive many morphogenetic processes throughout development, however, little is known about how apical constriction is regulated at the cellular and molecular level. Our preliminary studies of blastopore formation at the onset of Xenopus gastrulation identified specific candidate regulators of apical constriction and revealed a connection to Wnt signaling. We propose to identify novel components of the apical constriction pathway and evaluate the requirement for the identified candidate molecules in blastopore formation during gastrulation. These experiments will be carried out in Xenopus embryos, which are uniquely suited for biochemical, cell biological and functional analysis of this process in vivo. An unbiased and candidate-based expression cloning approach will be carried out to identify novel regulators of apical constriction and their role in apical constriction will e confirmed in loss-of-function studies. Based on epistatic analysis, these new molecular players will be positioned in a molecular pathway that leads to coordinate spatial regulation of Rho signaling and actomyosin contractility in the apical domains of epithelial cells. The proposed experiments will reconstruct molecular pathways leading to apical constriction in vertebrate epithelial cells during early development and establish a novel function for PCP proteins in apical constriction. These studies will contribute to the knowledge necessary for prevention of birth abnormalities such as neural tube closure defects and will be relevant to human cancer disease.