Myopia (short-sightedness) and hyperopia (long-sightedness) develop along different molecular pathways, according to a new study published Oct. 9 in the open-access journal PLOS biology by Andrei Tkatchenko of Columbia University and colleagues. The finding provides a new understanding of myopia, the most common form of visual impairment worldwide, and paves the way for drug development to prevent it.
Myopia occurs when the eye becomes too long, increasing the distance between the lens and the retina so that the image produced by the lens is focused at a point in front of the retina rather than on it. With hyperopia the opposite occurs; the eye is too short and the focal point is behind the retina. While prolonged “close work” such as reading or sewing increases the risk of myopia, neither the molecular pathways underlying its development nor the causes of hyperopia are well understood. Nearsightedness is expected to affect almost half of the world’s population in the next three decades.
To explore these pathways, the authors induced either myopia or hyperopia in common marmosets by placing lenses in front of their eyes. A lens that moves the focus behind the retina (“hyperopic defocus”) induces myopia, while a lens that moves it in front of the retina (“myopic defocus”) induces hyperopia. In either case, the eye changes shape, lengthening or shortening to compensate by moving the retina closer to focus.
When marmosets were exposed to defocusing of both species in one eye for up to 5 weeks, the activity of genes in the exposed retina changed compared to the unexposed retina (used as a control). However, the molecular pathways involved were, for the most part, different between the two types of defocusing. While both types of defocusing induced changes in key cellular signaling pathways, each affecting dozens of genes, only a small handful were affected by either type of defocusing. There were also differences in gene activity over time in each type, with little overlap between those affected within the first 10 days and those affected after 5 weeks. Importantly, the authors found that 29 of the genes whose activity changed in response to defocusing were located in chromosomal regions (called quantitative trait loci) previously associated with human myopia in large-scale genetic studies, suggesting that variations in the expression of genes involved in the normal regulation of eye shape in response to defocusing contribute to myopia.
“The results of this study demonstrate that the retina can distinguish between myopic and hyperopic defocus and responds to defocus of opposite signs by activating broadly different pathways,” Tkatchenko said. “The identification of these signaling pathways provides a framework for identifying new drug targets and developing more effective treatment options for myopia.”
Peer review / Experimental study / Animals
In your reporting, please use this URL to provide access to the freely available article in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2006021
Citation: Tkatchenko TV, Troilo D, Benavente-Perez A, Tkatchenko AV (2018) Gene Expression in Response to Optical Defocusing of Opposite Signs Reveals a Bidirectional Mechanism of Visually Guided Eye Growth. PLoS Biol 16(10):e2006021. https://doi.org/10.1371/journal.pbio.2006021
Caption: This image shows the effect of negative (green) and positive (red) lenses on eye growth and the heat map depicting clusters of genes differentially expressed in the retina in response to optical defocusing.
Photo credit: Andrei V. Tkatchenko, CC-BY
Funding: National Institutes of Health (NIH) (Grant Number R01EY023839). Obtained from AVT. The funder played no role in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript. National Institutes of Health (NIH) (grant number R01EY011228). Received from DT. The funder played no role in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript. National Institutes of Health (NIH) (grant number P30EY019007). Core Support for Vision Research Received from Columbia University Department of Ophthalmology. The funder played no role in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript. Blindness Prevention Research (New York, NY). Unrestricted funding received from Columbia University Department of Ophthalmology. The funder played no role in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.
Conflicts of Interest: The authors have declared no conflicts of interest.
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