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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM035527-29
Application #
8503496
Study Section
Intercellular Interactions (ICI)
Program Officer
Nie, Zhongzhen
Project Start
1990-07-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
29
Fiscal Year
2013
Total Cost
$658,344
Indirect Cost
$234,817
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
Collins, Caitlin; Nelson, W James (2015) Running with neighbors: coordinating cell migration and cell-cell adhesion. Curr Opin Cell Biol 36:62-70
Ladoux, B; Nelson, W J; Yan, J et al. (2015) The mechanotransduction machinery at work at adherens junctions. Integr Biol (Camb) 7:1109-19
Benham-Pyle, Blair W; Pruitt, Beth L; Nelson, W James (2015) Cell adhesion. Mechanical strain induces E-cadherin-dependent Yap1 and β-catenin activation to drive cell cycle entry. Science 348:1024-7
Bianchini, Julie M; Kitt, Khameeka N; Gloerich, Martijn et al. (2015) Reevaluating αE-catenin monomer and homodimer functions by characterizing E-cadherin/αE-catenin chimeras. J Cell Biol 210:1065-74
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
Cohen, Daniel J; Nelson, W James; Maharbiz, Michel M (2014) Galvanotactic control of collective cell migration in epithelial monolayers. Nat Mater 13:409-17
Dash, Surjya Narayan; Lehtonen, Eero; Wasik, Anita A et al. (2014) Sept7b is essential for pronephric function and development of left-right asymmetry in zebrafish embryogenesis. J Cell Sci 127:1476-86

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