miR-204 Induced Alterations in RPE/Retinal Structure and Function Mediated by Autophagic and Endo-lysosomal Activity: Implications for Homeostasis and Disease

Authors

• C Zhang
• KJ Miyagishima
• L Dong
• R Sharma
• A Rising
• R Dejene
• M Nimmagadda
• Y Wang
• A Maminishkis
• S Miller

Abstract

miR-204 is expressed in pulmonary, renal, mammary, and eye tissue, and its reduction can result in multiple diseases including cancer. We generated miR-204-/- mice to study the impact of miR-204 loss on retinal and retinal pigment epithelium (RPE) structure and function. In parallel experiments, we suppressed miR-204 expression in primary cultures of human RPE using anti-miR-204. The RPE is fundamentally important for maintaining the health and integrity of the retinal photoreceptors. miR-204-/- eyes evidenced areas of hypo-autofluorescence and defective photoreceptor digestion, along with increased microglia migration to the RPE. These migratory Iba1+ cells localized to the RPE apical surface where they participated in the phagocytosis of photoreceptor outer segments (POS) and contributed to a persistent buildup of undigested rhodopsin despite an increase in autophagy expression (RPE). More globally, these structural, molecular, and cellular outcomes were accompanied by an interruption of the visual cycle and decreased light-evoked electrical responses from the retina and RPE. In vitro suppression of miR-204 in human RPE altered LC3 associated phagocytosis by directly elevating the protein expression of LC3 and Rab22a thus reducing endosome maturation and POS clearance. Together, these experiments suggest that the normally high levels of miR-204 in RPE can mitigate disease onset by preventing generation of oxidative stress/inflammation originating from intracellular accumulation of undigested photoreactive POS lipids. More globally, these results implicate RPE miR-204 - mediated regulation of autophagy and endo-lysosomal interactions as a critical determinant of normal RPE/retina structure and function.

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