Molecular control of tissue morphogenesis

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DESCRIPTION (provided by applicant): A major challenge in developmental biology is to understand how large-scale changes in tissue structure are generated on a cellular and molecular level. Two decades of research in molecular genetics have provided insight into the mechanisms that control cell fate and patterning, but the morphogenetic events that translate cell fate determination into the shapes of cells and tissues are not well understood. A conserved feature of tissue architecture in vertebrates and invertebrates is a body axis that is elongated from head to tail. Polarized cell rearrangements play a major role in shaping the body axis of several organisms. Cell rearrangements in epithelial tissues are constrained by a network of adherens junctions between cells whose continuity is maintained throughout elongation. Unique strategies for tissue elongation may therefore be utilized by epithelial cells that must dynamicall remodel cell adhesion without compromising epithelial integrity. Recent work has provided insight into the physical mechanisms that underlie the mechanics of force generation and cell adhesion during axis elongation. In particular, many proteins that are required for axis elongation, including components of the contractile machinery and cell-cell junctions, are asymmetrically localized in the plane of the tissue. This asymmetric localization appears to be crucial for planar polarized force generation and junctional remodeling during axis elongation. However, the upstream signals that generate spatially regulated actomyosin contractility and adhesion to align cell rearrangements with the global tissue axes are not well understood. We have shown that Rho-kinase and Abl tyrosine kinase are asymmetrically localized and control the distribution of contractile forces and cell adhesion dynamics during axis elongation. We hypothesize that these kinases respond to upstream spatial cues to generate spatially regulated contractility and adhesion, polarized cell rearrangement, and tissue elongation. We will use molecular genetic, cell biological, and quantitative imaging approaches to investigate the upstream spatial mechanisms that regulate the localization and activity of these two conserved protein kinases that are essential for axis elongation. In addition, we will use computational methods and fluorescent protein imaging to study the dynamic mechanisms by which planar polarity is established and remodeled throughout elongation. Junctional remodeling is important for epithelial morphogenesis during development, and defects in epithelial maintenance and repair in the adult are associated with diseases such as cystic kidney disease and tumor cell metastasis. A better understanding of the mechanisms that regulate epithelial elongation can elucidate general principles of epithelial organ formation and provide insight into how the misregulation of these processes leads to human disease.