The long-term OBJECTIVE of our work is to gain a deep mechanistic understanding of the fundamental process of how a simple epithelium forms by defining how cell-cell adhesion initiates actin remodeling and polarized cell organization. Our RATIONALE is that a simple epithelium is the fundamental building block of metazoans and some non-metazoans. It comprises a closed monolayer of quiescent, functionally polarized cells held together by cell-cell adhesion complexes and surrounded by the extracellular matrix (ECM). Our results from the current period showed that the mechanistic link between cell-cell adhesion and epithelial polarity is ancient and fundamental to understanding how a simple epithelium forms. However, the current inventory of proteins and pathways involved in cadherin-mediated adhesion is likely incomplete, and is complicated by the overlapping roles of many of those proteins/pathways in other adhesion systems and cell migration. Our STRATEGY is to exploit the results of a novel genome-wide RNAi screen for Ca++- and E-cadherin-dependent cell-cell adhesion in Drosophila S2 cells that excluded Ca++-independent cell-cell adhesion, integrin-based ECM adhesion and spreading, and cell migration. Based on a stringent screen and validation protocol, we have provisionally assigned ~100 confirmed """"""""hits"""""""" to 6 intersecting regulatory """"""""hubs"""""""" that contain many proteins not previously associated directly with cadherin function. OUR GOALS in the next period are: 1). systematically define the functions of signaling pathways involved in cadherin-mediated cell-cell adhesion and the organization of epithelial polarity across a range of scales. We will use a prioritized list of proteins from the DE-cad/S2 screen, together with the spatial map and time line of protein reorganization during cell-cell adhesion defined in our previous work;and 2). Examine signaling pathways involved in the response of cell-cell adhesion complexes to perturbation of epithelial homeostasis upon mechanical strain, which results in the re-entry of quiescent cells into the cell cycle through different pathways that are dependent on E-cadherin, beta-catenin and alpha-catenin. We anticipate that our results will provide new a mechanistic understanding of pathways that regulate epithelial morphogenesis and homeostasis.
Understanding how cell-cell adhesion regulates the morphogenesis and homeostasis of simple epithelia is an important biomedical problem. Core components of the cadherin-catenin cell-cell adhesion complex are tumor suppressors and an oncogene. Defects in epithelial organization lead to a wide spectrum of genetic/metabolic diseases, with epithelial cancers being the most common type of cancer in humans.
|Bachir, Alexia I; Horwitz, Alan Rick; Nelson, W James et al. (2017) Actin-Based Adhesion Modules Mediate Cell Interactions with the Extracellular Matrix and Neighboring Cells. Cold Spring Harb Perspect Biol 9:|
|Clarke, Donald Nathaniel; Miller, Phillip W; Lowe, Christopher J et al. (2016) Characterization of the Cadherin-Catenin Complex of the Sea Anemone Nematostella vectensis and Implications for the Evolution of Metazoan Cell-Cell Adhesion. Mol Biol Evol 33:2016-29|
|Dickinson, Daniel J; Nelson, W James; Weis, William I (2015) Studying epithelial morphogenesis in Dictyostelium. Methods Mol Biol 1189:267-81|
|Sim, Joo Yong; Moeller, Jens; Hart, Kevin C et al. (2015) Spatial distribution of cell-cell and cell-ECM adhesions regulates force balance while main-taining E-cadherin molecular tension in cell pairs. Mol Biol Cell 26:2456-65|
|Ladoux, B; Nelson, W J; Yan, J et al. (2015) The mechanotransduction machinery at work at adherens junctions. Integr Biol (Camb) 7:1109-19|
|Bianchini, Julie M; Kitt, Khameeka N; Gloerich, Martijn et al. (2015) Reevaluating ?E-catenin monomer and homodimer functions by characterizing E-cadherin/?E-catenin chimeras. J Cell Biol 210:1065-74|
|Collins, Caitlin; Nelson, W James (2015) Running with neighbors: coordinating cell migration and cell-cell adhesion. Curr Opin Cell Biol 36:62-70|
|Benham-Pyle, Blair W; Pruitt, Beth L; Nelson, W James (2015) Cell adhesion. Mechanical strain induces E-cadherin-dependent Yap1 and ?-catenin activation to drive cell cycle entry. Science 348:1024-7|
|Toret, Christopher P; Collins, Caitlin; Nelson, W James (2014) An Elmo-Dock complex locally controls Rho GTPases and actin remodeling during cadherin-mediated adhesion. J Cell Biol 207:577-87|
|Lowndes, Molly; Rakshit, Sabyasachi; Shafraz, Omer et al. (2014) Different roles of cadherins in the assembly and structural integrity of the desmosome complex. J Cell Sci 127:2339-50|
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