Three-dimensional embryonic structures are patterned by coordinated cell movements and reorganization. Structural birth defects can arise by a number of cellular mechanisms, including genetic, epigenetic, and hormonal changes in the developing embryo. However, the ultimate cause of physical anomalies that arise during morphogenesis is atypical cell behavior. Studies in non-mammalian systems have revealed many conserved physical and molecular mechanisms driving embryonic cell reorganization, but important differences between organisms have also been described. Despite the central role that cell rearrangements play in embryonic development, the cellular and molecular events underlying planar polarized cell rearrangements in mammals are poorly understood. Epithelial cells of the developing mouse embryo undergo dramatic structural changes during gastrulation which are important for shaping the final form of the body axis. These cells have a relatively simple morphology and are located on the surface of the embryo, where they are readily accessible for live imaging. These aspects of early epithelial development make this tissue uniquely well-suited for studying mammalian epithelial morphogenesis. To identify the mechanisms driving tissue shape changes during epithelial reorganization in the developing mouse embryo, cell biological and computational methods will be used to analyze changes in cell shape, topology, and polarity during this process. I will test the hypothesis that planar polarized actomyosin and cell adhesion activities are required for remodeling of the embryonic epithelium by quantifying the spatiotemporal localization of cytoskeletal, adhesive, and regulatory proteins. Candidate regulators of cell polarity will be investigated using genetic analysis. Live imaging methods using time-lapse confocal imaging on cultured mouse embryos will be applied to elucidate the cell behaviors that drive epithelial remodeling in real time in the developing mouse embryo, and individual cells will be tracked over time with single-cell resolution. In addition to advancing our knowledge of tissue morphogenesis during early mouse embryonic development, the long-term goal of these studies is to inform our understanding of polarized cell behaviors in mammals and how they compare to those of other animals. Elucidating the mechanisms of epithelial remodeling in the mouse embryo has the potential to inform our understanding of the basic cell biological processes that drive embryonic development, especially during extensive reorganizations that shape tissues in the embryo. These findings are likely to uncover mechanisms of embryonic morphogenesis that are conserved among animals, from flies to mice, as well as processes that are unique to mammals. A richer understanding of polarized, coordinated cell behaviors in the mouse embryo has the potential to reveal conserved cellular and molecular processes that are affected in cases of congenital and acquired diseases that involve aberrant behaviors of large cell populations.
Miscommunication between neighboring cells, both next-door and long-distance neighbors, is often responsible for structural congenital anomalies such as heart and neural tube defects in humans. Although these mechanisms are understood in other animals, we know very little about how the behaviors of individual cells in mammalian embryos are coordinated to produce the highly specialized, intricately patterned tissues of mature organs. The research in this application is aimed at identifying the behaviors and molecules that link changes in individual cells to the generation of an elaborate, three-dimensional tissue structure during embryonic development in the mouse.
