E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning

• Published in: Nature communications Vol. 8; no. 1; pp. 1250 - 16
• Main Authors: Rübsam, Matthias, Mertz, Aaron F., Kubo, Akiharu, Marg, Susanna, Jüngst, Christian, Goranci-Buzhala, Gladiola, Schauss, Astrid C., Horsley, Valerie, Dufresne, Eric R., Moser, Markus, Ziegler, Wolfgang, Amagai, Masayuki, Wickström, Sara A., Niessen, Carien M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/80/79/1987; 631/80/79/2028; 631/80/79/2066; 631/80/86/2368; Ablation; Actin; Actin Cytoskeleton - metabolism; Actins - metabolism; Adherens Junctions - metabolism; Adherens Junctions - ultrastructure; Animals; Atomic force microscopy; Cadherins - metabolism; Cell Differentiation; Cell Proliferation; Complex formation; Contractility; Cytoskeleton; E-cadherin; Epidermal growth factor receptors; Epidermis; Epidermis - metabolism; Epidermis - ultrastructure; ErbB Receptors - metabolism; Humanities and Social Sciences; Mechanotransduction; Mechanotransduction, Cellular; Mice; Mice, Knockout; Microscopy; Microscopy, Atomic Force; multidisciplinary; Multilayers; Polarization; Positioning devices (machinery); Science; Science (multidisciplinary); Signal Transduction; Signaling; Stability; Tension; Tight junctions; Tight Junctions - metabolism; Tight Junctions - ultrastructure; Traction force
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01170-7

Generation of a barrier in multi-layered epithelia like the epidermis requires restricted positioning of functional tight junctions (TJ) to the most suprabasal viable layer. This positioning necessitates tissue-level polarization of junctions and the cytoskeleton through unknown mechanisms. Using quantitative whole-mount imaging, genetic ablation, and traction force microscopy and atomic force microscopy, we find that ubiquitously localized E-cadherin coordinates tissue polarization of tension-bearing adherens junction (AJ) and F-actin organization to allow formation of an apical TJ network only in the uppermost viable layer. Molecularly, E-cadherin localizes and tunes EGFR activity and junctional tension to inhibit premature TJ complex formation in lower layers while promoting increased tension and TJ stability in the granular layer 2. In conclusion, our data identify an E-cadherin-dependent mechanical circuit that integrates adhesion, contractile forces and biochemical signaling to drive the polarized organization of junctional tension necessary to build an in vivo epithelial barrier.
In multi-layered epithelia tight junctions (TJ) are confined to the most suprabasal viable layer. Here the authors show that this is regulated by ubiquitously localized E-cadherin tuning junctional tension and EGFR activity to inhibit TJ formation in lower layers while promoting TJ stability in the granular layer 2.