Micro-RNAs (miRNAs) are members of the family of noncoding RNA molecules that regulate gene expression by translational repression and mRNA degradation. Initial identification of miRNAs revealed them only as developmental regulators; later, their radiated roles in various cellular processes have been established. They regulate several pathways, including developmental timing, hematopoiesis, organogenesis, apoptosis, cell differentiation and proliferation. Their roles in eye disorders are being explored by biologists around the world. Eye physiology requires the perfect orchestration of all the regulatory networks; any defect in any of the networks leads to eye disorders. The dysregulation of miRNA expression has been reported in many eye disorders, which paves the way for new therapeutics. This review summarizes the biogenesis of miRNAs and their role in eye disorders. miRNA studies also have implications for the understanding of various complex metabolic pathways leading to disorders of the eye. The ultimate understanding leads to potential opportunities in evaluating miRNAs as molecular biomarkers, prognostic tools, diagnostic tools and therapeutic agents for eye disorders.

1.
Pasquinelli AE, Hunter S, Bracht J: MicroRNAs: a developing story. Curr Opin Genet Dev 2005;15:200-205.
2.
Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215-233.
3.
Lee RC, Feinbaum RL, Ambros V: The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993;75:843-854.
4.
Wightman B, Ha I, Ruvkun G: Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 1993;75:855-862.
5.
Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ: miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006;34:D140-D144.
6.
Olena AF, Patton JG: Genomic organization of microRNAs. J Cell Physiol 2010;222:540-545.
7.
Araud T: Overview of the miRNA Pathways; honours thesis, University of Geneva, 2008.
8.
Kim VN, Nam JW: Genomics of microRNA. Trends Genet 2006;22:165-173.
9.
Catalucci D, Gallo P, Condorelli G: MicroRNAs in cardiovascular biology and heart disease. Circ Cardiovasc Genet 2009;2:402-408.
10.
Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN: MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004;23:4051-4060.
11.
Kim VN: Small RNAs: classification, biogenesis, and function. Mol Cell 2005;19:1-15.
12.
Cullen BR: Transcription and processing of human microRNA precursors. Mol Cell 2004;16:861-865.
13.
Kim VN: MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 2005;6:376-385.
14.
Davis BN, Hata A: Regulation of microRNA biogenesis: a miRiad of mechanisms. Cell Commun Signaling 2009;7:18.
15.
He L, Hannon GJ: MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004;5:522-531.
16.
Carthew RW: Gene regulation by microRNAs. Curr Opin Genet Dev 2006;16:203-208.
17.
De Longh RU, Wederell E, Lovicu FJ, McAvoy JW: Transforming growth factor-beta-induced epithelial-mesenchymal transition in the lens: a model for cataract formation. Cells Tissues Organs 2005;179:43-55.
18.
Dunmire JJ, Laquoros E, Bouhenni RA, Jones M, Edward DP: MicroRNA in aqueous humor from patients with cataract. Exp Eye Res 2013;108:68-71.
19.
Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ, Wang K: The microRNA spectrum in 12 body fluids. Clin Chem 2010;56:1733-1741.
20.
Kubo E, Hasanova N, Sasaki H, Singh DP: Dynamic and differential regulation in the microRNA expression in the developing and mature cataractous rat lens. J Cell Mol Med 2013;17:1146-1159.
21.
Lang R, McAvoy JW: Growth factors in lens development; in Lovicu FJ, Robinson ML (eds): Development of the Ocular Lens. New York, Cambridge University Press, 2004, pp 261-289.
22.
Saika S, Miyamoto T, Ishida I, Shirai K, Ohnishi Y, Ooshima A, McAvoy J W: TGFβ-Smad signalling in postoperative human lens epithelial cells. Br J Ophthalmol 2002;86:1428-1433.
23.
Saika S: TGFβ pathobiology in the eye. Lab Invest 2006;86:106-115.
24.
Hoffmann A, Huang Y, Suetsugu-Maki R, Ringelberg CS, Tomlinson CR, Del Rio-Tsonis K, Tsonis PA: Implication of the miR-184 and miR-204 competitive RNA network in control of mouse secondary cataract. Mol Med 2012;18:528-538.
25.
Wang Y, Li W, Zang X, Chen N, Liu T, Tsonis PA, Huang Y: MicroRNA-204-5p regulates epithelial-to-mesenchymal transition during human posterior capsule opacification by targeting SMAD4. Invest Ophthalmol Vis Sci 2013;54:323-332.
26.
Dong N, Xu B, Benya SR, Tang X: MiRNA-26b inhibits the proliferation, migration and epithelial-mesenchymal transition of lens epithelial cells. Mol Cell Biochem 2014;396:229-238.
27.
Shaham O, Gueta K, Mor E, Oren-Giladi P, Grinberg D, Xie Q, Cveki A, Shomron N, Davis N, Keydar-Prizant M, Raviv S, Pasmanik-Chor M, Bell RE, Levy C, Avellino R, Banfi S, Conte I, Ashery-Padan R: Pax6 regulates gene expression in the vertebrate lens through miR-204. PLoS Genet 2013;9:e1003357.
28.
Liang CL, Hsi E, Chen KC, Pan YR, Wang YS, Juo SH: A functional polymorphism at 3′UTR of the PAX6 gene may confer risk for extreme myopia in the Chinese. Invest Ophthalmol Vis Sci 2011;52:3500-3505.
29.
Chen KC, Hsi E, Hu CY, Chou WW, Liang CL, Juo SH: MicroRNA-328 may influence myopia development by mediating the PAX6 gene. Invest Ophthalmol Vis Sci 2012;53:2732-2739.
30.
Qiu R, Liu Y, Wu JY, Liu K, Mo W, He R: Misexpression of miR-196a induces eye anomaly in Xenopus laevis. Brain Res Bull 2009;79:26-31.
31.
Macklin MT: A study of retinoblastoma in Ohio. Am J Hum Genet 1960;12:1-43.
32.
Wang J, Wang X, Wu G, Hou D, Hu Q: MiR-365b-3p, down-regulated in retinoblastoma, regulates cell cycle progression and apoptosis of human retinoblastoma cells by targeting PAX6. FEBS Lett 2013;587:1779-1786.
33.
Conkrite K, Sundby M, Mukai S, Thomson JM, Mu D, Hammond SM, MacPherson D: miR-17-92 cooperates with TB pathway mutations to promote retinoblastoma. Gene Dev 2011;16:1734-1745.
34.
Sage J, Ventura A: miR than meets the eye. Gene Dev 2011;25:1663-1667.
35.
Petrocca F, Vecchione A, Croce CM: Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor β signaling. Cancer Res 2008;68:8191-8194.
36.
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM: A microRNA polycistron as a potential human oncogene. Nature 2005;435:828-833.
37.
Olive V, Jiang I, He L: miR-17-92, a cluster of miRNAs in the midst of the cancer network. Int J Biochem Cell Biol 2010;42:1348-1354.
38.
Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 2006;103:2257-2261.
39.
Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Yatabe Y, Kawahara K, Sekido Y, Takahashi T: A polycistronic microRNA cluster, miR-19-72, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 2005;65:9628-9632.
40.
Corney DC, Flesken-Nikitin A, Godwin AK, Wang W, Nikitin AY: MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Res 2007;67:8433-8438.
41.
Zhao JJ, Yang J, Lin J, Yao N, Zhu Y, Zheng J, Xu J, Cheng JQ, Lin JY, Ma X: Identification of miRNAs associated with tumorigenesis of retinoblastoma by miRNA microarray analysis. Child Nerv Syst 2009;25:13-20.
42.
Jo DH, Kim JH, Park WY, Kim KW, Yu YS, Kim JH: Differential profiles of microRNAs in retinoblastoma cell lines of different proliferation and adherence patterns. J Pediatr Hematol Oncol 2011;33:529-533.
43.
Dalgard CL, Gonzalez M, deNiro JE, O'Brien JM: Differential microRNA-34a expression and tumor suppressor function in retinoblastoma cells. Invest Ophthalmol Vis Sci 2009;50:4542-4551.
44.
Martin J, Bryar P, Mets M, Weinstein J, Jones A, Martin A, Vanin EF, Scholtens D, Costa FF, Soares MB, Laurie NA: Differentially expressed miRNAs in retinoblastoma. Gene 2013;512:294-299.
45.
Lukiw WJ, Surjyadipta B, Dua P, Alexandrov PN: Common micro RNAs (miRNAs) target complement factor H (CFH) regulation in Alzheimer's disease (AD) and in age-related macular degeneration (AMD). Int J Biochem Mol Biol 2012;3:105-116.
46.
Li YY, Cui JG, Dua P, Pogue AI, Bhattacharjee S, Lukiw WJ: Differential expression of miRNA-146a-regulated inflammatory genes in human primary neural, astroglial and microglial cells. Neurosci Lett 2011;499:109-113.
47.
Pogue AI, Percy ME, Cui JG, Li YY, Bhattacharjee S, Hill JM, Kruck TPA, Zhao Y, Lukiw WJ: Up-regulation of NF-kB-sensitive miRNA-125b and miRN-146a in metal sulfate-stressed human astroglial (HAG) primary cell cultures. J Inorg Biochem 2011;105:1434-1437.
48.
Li YY, Alexandrov PN, Pogue AI, Zhao Y, Bhattacharhee S, Lukiw WJ: miRNA-155 up-regulation and complement factor H deficits in Down's syndrome. Neuroreport 2012;23:168-173.
49.
Pogue AI, Cui JG, Li YY, Zhao Y, Culichhia F, Lukiw WJ: miRNA-125b (miRNA-125b) function is astrogliosis and glial cell proliferation. Neurosci Lett 2010;476:18-22.
50.
Hebert SS, De Strooper B: Alterations of the microRNA network cause neurodegenerative disease. Trends Neurosci 2009;32:199-206.
51.
Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Jaworski C, Duncan T, Cameron JE, Flemington EK, Hooks JJ, Redmond TM: Differential regulation of microRNA-146a and microRNA-146b-5p in human retinal pigment epithelial cells by interleukin-1β, tumor necrosis factor-α and interferon-γ. Mol Vis 2013;19:737-750.
52.
Ertekin S, Yildirim O, Dinc E, Ayaz L, Fidanci SB, Tamer L: Evaluation of circulating miRNAs in wet age-related macular degeneration. Mol Vis 2014;20:1057-1066.
53.
Winkler BS, Boulton ME, Gottsch JD, Sternberg P: Oxidative damage and age-related macular degeneration. Mol Vis 1999;5:32.
54.
Williams DL: Oxidative stress and the eye. Vet Clin North Am Small Animal Pract 2008;38:179-192, vii.
55.
Cai J, Nelson KC, Wu M, Sternberg P Jr, Jones DP: Oxidative damage and protection of the RPE. Prog Retinal Eye Res 2000;19:205-221.
56.
Wiktorowska-Owczarck A, Nowak JZ: Pathogenesis and prophylaxis of AMD: focus on oxidative stress and antioxidants (in Polish). Postepy Hig Med Dosw (Online) 2010;64:333-343.
57.
Janik-Papis K, Ulinska M, Krzyzanowska A, Stockzynska E, Borucka AI, Wozniak K, Malgorzata Z, Szaflik JP, Blasiak J: Role of oxidative mechanisms in the pathogenesis of age-related macular degeneration (in Polish). Klinika Oczna 2009;111:168-173.
58.
Hinton DR, He S, Lopez PF: Apoptosis in surgically excised choroidal neovascular membranes in age-related macular degeneration. Arch Ophthalmol 1998;116:203-209.
59.
Jiang S, Wu MW, Sternberg P, Jones DP: Fas mediates apoptosis and oxidant-induced cell death in cultured hRPE cells. Invest Ophthalmol Vis Sci 2000:41:645-655.
60.
Kawa M, Machalinska A: The role of microRNA in the pathogenesis of age-related macular degeneration: its pathophysiology and potential pharmacological aspects. J Biochem Pharmacol Res 2014;2:21-32.
61.
Lin H, Qian J, Castillo AC, Long B, Keyes KT, Chen G, Ye Y: Effect of miR-23 on oxidant-induced injury in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 2011;52:6308-6314.
62.
Shen J, Yang X, Xie B, Chen Y, Swaim M, Hackett SF, Campochiaro PA: MicroRNAs regulate ocular neovascularization. Mol Ther J Am Soc Gene Ther 2008;16:1208-1216.
63.
Li T, Snyder WK, Olsson JE, Dryja TP: Transgenic mice carrying the dominant rhodopsin mutation P347S: evidence for defective vectorial transport of rhodopsin to the outer segments. Proc Natl Acad Sci USA 1996;93:14176-14181.
64.
Loscher CJ, Hokamp K, Kenna PF, Ivens AC, Humphries P, Palfi A, Farrar GJ: Altered retinal microRNA expression profile in a mouse model of retinitis pigmentosa. Genome Biol 2007;8:R248.
65.
Mastropasqua R, Toto L, Cipollone F, Santovito D, Carpineto P, Mastropasqua L: Role of microRNAs in the modulation of diabetic retinopathy. Prog Retinal Eye Res 2014;43:92-107.
66.
Long JY, Wang Y, Wang WJ, Chang BHJ, Danesh FR: Identification of microRNA-93 as a novel regulator of vascular endothelial growth factor in hyperglycemic conditions. J Biol Chem 2010;285:23455-23463.
67.
Iliff BW, Gottsch JD, Riazuddin SA: A Single-base substitution in the seed region of miR-184 causes EDICT syndrome. Invest Ophthalmol Vis Sci 2012;53:348-353.
68.
Engelsvold D, Utheim T: miRNA and mRNA expression profiling identifies members of the miR-200 family as potential regulators of epithelial-mesenchymal transition in pterygium. Exp Eye Res 2013;115:189-198.
69.
Zhou Q, Xiao X, Wang C, Zhang X, Li F, Zhou Y, Kijlstra A, Yang P: Decreased microRNA-15 expression in ocular Behçet's disease but not in Vogt Koyanagi Harada syndrome. Invest Ophthalmol Vis Sci 2012;53:5665-5674.
70.
Wei L, Zhou Q, Hou S, Bai L, Liu Y, Qi J, Xiang Q, Zhou Y, Kijlstra A, Yang P: MicroRNA-146a and Ets-1 gene polymorphisms are associated with pediatric uveitis. PLoS One 2014;9:e91199.
71.
Yu H, Liu Y, Bai L, Kijlstra A, Yang P: Predisposition to Behçet's disease and VKH syndrome by genetic variants of miR-182. J Mol Med 2014;92:961-967.
72.
Tarrant TK, Silver PB, Wahlsten JL, Rizzo L, Chan CC, Wiggert B, Caspi RR: Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis. J Exp Med 1999;189:219-230.
73.
Ishida W, Fukuda K, Higuchi T, Kajisako M, Sakamoto S, Fukushima A: Dynamic changes of microRNAs in the eye during the development of experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 2011;52:611-617.
74.
Chen X, He D, Dong XD, Dong F, Wang J, Wang L, Tanq J, Hu DN, Yan D, Tu L: MicroRNA-124a is epigenetically regulated and acts as a tumor suppressor by controlling multiple targets in uveal melanoma. Invest Ophthalmol Vis Sci 2013;54:2248-2256.
75.
Yan D, Dong XD, Chen X, Yao S, Wang L, Wang J, Wang C, Hu DN, Qu J, Tu L: Role of microRNA-182 in posterior uveal melanoma: regulation of tumor development through MITF, BCL2 and cyclin D2. PLoS One 2012;7:e40967.
76.
Achberger S, Aldrich W, Tubbs R, Crabb JW, Singh AD, Triozzi PL: Circulating immune cell and microRNA in patients with uveal melanoma developing metastatic disease. Mol Immunol 2104;58:182-186.
77.
Li G, Luna C, Qiu J, Epstein DL, Gonzalez P: Targeting of integrin β1 and kinesin 2α by microRNA 183. J Biol Chem 2010;285:5461-5471.
78.
Luna C, Li G, Qiu J, Epstein DL, Gonzalez P: Role of miR-29b on the regulation of the extracellular matrix in human trabecular meshwork cells under chronic oxidative stress. Mol Vis 2009;15:2488-2497.
79.
Villarreal G Jr, Oh DJ, Kang MH, Rhee DJ: Coordinated regulation of extracellular matrix synthesis by the microRNA-29 family in the trabecular meshwork. Invest Ophthalmol Vis Sci 2011;52:3391-3397.
80.
Saika S: TGFβ pathobiology in the eye. Lab Invest 2006;86:106-115.
81.
Fuchshofer R, Stephan DA, Russell P, Tamm ER: Gene expression profiling of TGFβ2-and/or BMP7-treated trabecular meshwork cells: identification of Smad7 as a critical inhibitor of TGF-β2 signaling. Exp Eye Res 2009;88:1020-1032.
82.
Luna G, Li G, Qiu J, Epstein DL, Gonzalez P: MicroRNA-24 regulates the processing of latent TGFβ1 during cyclic mechanical stress in human trabecular meshwork cells through direct targeting of FURIN. J Cell Physiol 2011;226:1407-1414.
83.
Tanaka Y, Tsuda S, Kunikata H, Sato J, Kokubun T, Yasuda M, Nishiquchi KM, Inada T, Nakazawa T: Profiles of extracellular miRNAs in the aqueous humor of glaucoma patients assessed with a microarray system. Sci Rep 2014;4:5089.
84.
Elhalis H, Azizi B, Jurkunas UV: Fuchs endothelial corneal dystrophy. Ocular Surface 2010;8:173-184.
85.
Adamis AP, Filatov V, Tripathi BJ, Tripathi RC: Fuchs' endothelial dystrophy of the cornea. Surv Ophthalmol 1993;38:149-168.
86.
Matthaei J, Hu J, Kallay L, Eberhart CG, Cursiefen C, Qian J, Lackner EM, Jun AS: Endothelial cell microRNA expression in human late-onset Fuchs' dystrophy. Invest Ophthalmol Vis Sci 2014;55:216-225.
87.
Wang B, Komers R, Carew R, Winbanks CE, Xu B, Herman-Edelstein M, Koh P, Thomas M, Jandeleit-Dahm K, Gregorevic P, Cooper ME, Kantharidis P: Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis. J Am Soc Nephrol 2012;23:252-265.
88.
Koizumi N, Okumura N, Ueno M, Nakagawa H, Hamuro J, Kinoshita S: Rho-associated kinase inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy. Cornea 2013;32:1167-1170.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.