MicroRNA‐mRNA genetic networks in refractive eye development and myopia

Abstract

AbstractPurposeMyopia is a complex disease controlled by both environmental and genetic factors. Recent genetic studies suggested that the development of myopia is controlled by numerous coding genes. However, the contribution of non‐coding genes, such as microRNAs, is poorly understood. The purpose of this study was to investigate the role of microRNAs in refractive eye development and the development of myopia.MethodsDifferential expression of both microRNAs and mRNAs was analyzed in the retina, RPE, choroid, and sclera of C57BL mice upon induction of experimental myopia with −20 D lenses using RNA‐seq and microRNA‐mRNA genetic networks were reconstructed. We also explored the impact of microRNAs on signaling pathways and evaluated the role of microRNAs in refractive eye development in vivo using conditional Dicer1 knockout mice.ResultsGene expression profiling revealed large number of differential mRNAs and microRNAs in the retina and RPE/choroid/sclera complexes. MicroRNAs were involved in the regulation of several key canonical pathways and biological processes previously implicated in refractive eye development. We then compared visual acuity, contrast sensitivity, and refractive errors in Dicer1 knockouts (Dicer1−/−) and wild‐type littermates (Dicer1+/+) at baseline. We found that loss of miRNAs in the postnatal eyes resulted in a large hyperopic shift in refractive error (+16.3 ± 3.6 D in Dicer1 knockouts versus +4.7 ± 3.0 D in wild‐type animals, p < 1.44 × 10−4), which was accompanied by a small reduction in visual acuity (0.360 ± 0.006 cpd in Dicer1−/− versus 0.403 ± 0.002 cpd in Dicer1+/+, p < 1.16 × 10−7) and contrast sensitivity (12.01 ± 0.27 in Dicer1−/− versus 13.65 ± 0.40 in Dicer1+/+, p < 1.91 × 10−5). Loss of miRNAs also caused a statistically significant increase in susceptibility to form‐deprivation myopia in Dicer1 knockouts compared to wild‐type animals (−19.1 ± 6.8 D in Dicer1−/− versus −9.7 ± 2.7 D in Dicer1+/+, p < 1.51 × 10−4).ConclusionsOur data suggest that microRNAs play significant role in refractive eye development and the development of myopia via modulation of several canonical signaling pathways. MicroRNAs appear to be integrated in the signaling cascade involved in the optical‐defocus‐regulated refractive eye development at multiple levels.