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The Tight Junction Associated Signalling Proteins ZO-1 and ZONAB Regulate Retinal Pigment Epithelium Homeostasis in Mice

Georgiadis, A; Tschernutter, M; Bainbridge, JWB; Balaggan, KS; Mowat, F; West, EL; Munro, PMG; ... Ali, RR; + view all (2010) The Tight Junction Associated Signalling Proteins ZO-1 and ZONAB Regulate Retinal Pigment Epithelium Homeostasis in Mice. PLOS ONE , 5 (12) , Article e15730. 10.1371/journal.pone.0015730. Green open access

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Abstract

Cell-cell adhesion regulates the development and function of epithelia by providing mechanical support and by guiding cell proliferation and differentiation. The tight junction (TJ) protein zonula occludens (ZO)-1 regulates cell proliferation and gene expression by inhibiting the activity of the Y-box transcription factor ZONAB in cultured epithelial cells. We investigated the role of this TJ-associated signalling pathway in the retinal pigment epithelium (RPE) in vivo by lentivirally-mediated overexpression of ZONAB, and knockdown of its cellular inhibitor ZO-1. Both overexpression of ZONAB or knockdown of ZO-1 resulted in increased RPE proliferation, and induced ultrastructural changes of an epithelial-mesenchymal transition (EMT)-like phenotype. Electron microscopy analysis revealed that transduced RPE monolayers were disorganised with increased pyknosis and monolayer breaks, correlating with increased expression of several EMT markers. Moreover, fluorescein angiography analysis demonstrated that the increased proliferation and EMT-like phenotype induced by overexpression of ZONAB or downregulation of ZO-1 resulted in RPE dysfunction. These findings demonstrate that ZO-1 and ZONAB are critical for differentiation and homeostasis of the RPE monolayer and may be involved in RPE disorders such as proliferative vitroretinopathy and atrophic age-related macular degeneration.

Type: Article
Title: The Tight Junction Associated Signalling Proteins ZO-1 and ZONAB Regulate Retinal Pigment Epithelium Homeostasis in Mice
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0015730
Publisher version: http://dx.doi.org/10.1371/journal.pone.0015730
Language: English
Additional information: © 2010 Georgiadis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This project was supported by the European Union (Integrated Project EVI-GENORET: LSHG-CT-2005-512036), Medical Research Council and the National Institute for Health Research Biomedical Centre for Ophthalmology. JWBB is a Wellcome Trust Advanced Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: BOX-BINDING PROTEIN, MESENCHYMAL TRANSITION, PROLIFERATIVE VITREORETINOPATHY, DIABETIC-RETINOPATHY, CELL-PROLIFERATION, GENE-EXPRESSION, E-CADHERIN, TRANSCRIPTION, BARRIER, DIFFERENTIATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/703054
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