MicroRNA-184 promotes differentiation of the retinal pigment epithelium by targeting the AKT2/mTOR signaling pathway
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Chao Jiang1, Bing Qin1,2, Guohua Liu3, Xiantao Sun4, Houxia Shi1, Sijia Ding1, Yuan Liu5, Meidong Zhu6, Xue Chen1, Chen Zhao1,7,8
1Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
2Department of Ophthalmology, The First People’s Hospital of Suqian, Suqian, China
3Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, China
4Department of Ophthalmology, Children’s Hospital of Zhengzhou, Zhengzhou, China
5Department of Ophthalmology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
6Save Sight Institute, Discipline of Clinical Ophthalmology and Eye Health (CO9), The University of Sydney, Sydney, Australia
7Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China
8State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat Sen University, Guangzhou, China
Chen Zhao, email: [email protected]
Xue Chen, email: [email protected]
Keywords: miR-184, retinal pigment epithelium, differentiation, AKT2, mTOR
Received: February 14, 2016 Accepted: June 30, 2016 Published: July 13, 2016
Dedifferentiation of retinal pigment epithelium (RPE) cells is a crucial contributing factor to the pathology of retinal degenerative diseases, including age-related macular degeneration (AMD). Herein, we aim to reveal the roles of microRNAs (miRNAs) in RPE dedifferentiation and seek for potential therapeutic targets. Based on the microarray data, miR-184 was sorted out as the most up-regulated signature along with the differentiation from human induced pluripotent stem cells (hiPSC) to RPE cells, suggesting its potential promotive role in RPE differentiation. In vitro study indicated that miR-184 insufficiency suppressed RPE differentiation, typified by reduction of RPE markers, and promoted cell proliferation and migration. The role of miR-184 in maintaining regular RPE function was further proved in zebrafish studies. We also noticed that miR-184 expression was reduced in the macular RPE-choroid from a donor with RPE dysfunction compared to a healthy control. We next demonstrated that RAC-beta serine/threonine-protein kinase (AKT2) was a direct target for miR-184. MiR-184 promoted RPE differentiation via suppression of AKT2/mammalian target of rapamycin (mTOR) signaling pathway. We also found that AKT2 was up-regulated in macular RPE-choroid of the donor with RPE dysfunction and dry AMD patients. Taken together, our findings suggest that miR-184 insufficiency is involved in the pathogenesis of dry AMD. MiR-184 promotes RPE differentiation via inhibiting the AKT2/mTOR signaling pathway. MiR-184 based supplementary therapeutics and mTOR blocker, like rapamycin, are prospective options for AMD treatment.
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