Spatiotemporal regulation of mechanical networks drives coordinated epithelial cell shape changes

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Project Summary Epithelial tissues serve diverse functions in many organs. To function properly in their physiological contexts, epithelial tissues frequently must adopt specialized cell geometries. Therefore, understanding the molecular underpinnings of the morphogenetic programs that generate these geometries is of utmost importance to understanding epithelial biology. The most energetically favorable organization of cells in an epithelium is a hexagonal packing. Generating more complex cellular geometries requires (1) force-generating effectors that provide the mechanical input to reach the higher energy state and (2) polarity factors that spatially and temporally coordinate force-generating effectors. To understand the mechanisms underlying these two aspects of morphogenesis, I study a dramatic alignment of cells in the Drosophila embryonic epithelium. This event generates straight columns of rectangular cells with junctions aligning along one axis of the embryo. This cell geometry is very energetically unfavorable. Because confounding morphogenetic processes such as cell division and delamination do not occur during alignment, this epithelium is an excellent system for studying coordinated cell shape changes. I hypothesize that the coordinated cell shape changes that take place during alignment are driven by anisotropic distribution of cortical tension. This anisotropy is generated by planar polarization of the contractile actomyosin cytoskeleton. For my first aim, I will investigate the mechanical basis of alignment. I have found that cortical tension is elevated along aligning junctions, supporting my hypothesis that force anisotropy underlies this process. I will first determine whether this force anisotropy is required for alignment and whether a polarized actomyosin cytoskeleton is the source of this mechanical asymmetry. I will then identify the actin regulators that control the formation and activity of polarized actomyosin assemblies. The second goal of my project is to identify the polarity factors that govern alignment. My preliminary data suggests that the Rho Kinase/Par3 polarity module is required for the orientation of actomyosin assemblies. In addition to testing this hypothesis, I will assess the role of phosphoinositide signaling in alignment. Recent evidence I have uncovered indicates that asymmetric phosphoinositide signaling regulates actin remodeling and that this asymmetry is a novel downstream intermediate of ROK/Par3. My proposed research will work towards uncovering a novel pathway of coordinated cell shape changes that will be applicable to many other morphogenetic processes.