title: Chloride intracellular channel 4 is critical for the epithelial morphogenesis of RPE cells and retinal attachment.
abstract: Retinal detachment is a sight-threatening condition. The molecular mechanism underlying the adhesion between the RPE and photoreceptors is poorly understood because the intimate interactions between these two cell types are impossible to model and study in vitro. In this article, we show that chloride intracellular channel 4 (CLIC4) is enriched at apical RPE microvilli, which are interdigitated with the photoreceptor outer segment. We used a novel plasmid-based transfection method to cell-autonomously suppress CLIC4 in RPE in situ. CLIC4 silenced RPE cells exhibited a significant loss of apical microvilli and basal infoldings, reduced retinal adhesion, and epithelial-mesenchymal transition. Ectopically expressing ezrin failed to rescue the morphological changes exerted by CLIC4 silencing. Neural retinas adjacent to the CLIC4-suppressed RPE cells display severe dysplasia. Finally, a high level of aquaporin 1 unexpectedly appeared at the apical surfaces of CLIC4-suppressed RPE cells, together with a concomitant loss of basal surface expression of monocarboxylate transporter MCT3. Our results suggested that CLIC4 plays an important role in RPE-photoreceptor adhesion, perhaps by modulating the activity of cell surface channels/transporters. We propose that these changes may be attributable to subretinal fluid accumulation in our novel retinal detachment animal model.
authors.affiliation: Department of Ophthalmology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Jen-Zen
authors.initials: JZ
authors.lastname: Chuang
authors.forename: Szu-Yi
authors.initials: SY
authors.lastname: Chou
authors.forename: Ching-Hwa
authors.initials: CH
authors.lastname: Sung
mesh_terms: D000818:Animals; D001284:Atrophy; D002448:Cell Adhesion; D002460:Cell Line; D018118:Chloride Channels / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D020868:Gene Silencing; D006801:Humans; D008871:Microvilli / Q000378:metabolism / Q000648:ultrastructure; D009024:Morphogenesis; D010641:Phenotype; D010857:Pigment Epithelium of Eye / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000099149:Ezrin
chemical_list: D018118:Chloride Channels; D003598:Cytoskeletal Proteins; D000099149:Ezrin; C467578:Clic4 protein, rat