title: The tight junction associated signalling proteins ZO-1 and ZONAB regulate retinal pigment epithelium homeostasis in mice.
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.
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgiadis
authors.forename: Marion
authors.initials: M
authors.lastname: Tschernutter
authors.forename: James W B
authors.initials: JW
authors.lastname: Bainbridge
authors.forename: Kamaljit S
authors.initials: KS
authors.lastname: Balaggan
authors.forename: Freya
authors.initials: F
authors.lastname: Mowat
authors.forename: Emma L
authors.initials: EL
authors.lastname: West
authors.forename: Peter M G
authors.initials: PM
authors.lastname: Munro
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Karl
authors.initials: K
authors.lastname: Matter
authors.forename: Maria S
authors.initials: MS
authors.lastname: Balda
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
mesh_terms: D000792:Angiography / Q000379:methods; D000818:Animals; D002448:Cell Adhesion; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D008268:Macular Degeneration / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron / Q000379:methods; D010750:Phosphoproteins / Q000378:metabolism*; D012164:Retinal Diseases / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D062826:Zonula Occludens-1 Protein
chemical_list: C408323:Csda protein, mouse; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C569043:Tjp1 protein, mouse; D014157:Transcription Factors; D062826:Zonula Occludens-1 Protein