Gene expression in response to optical defocus of opposite signs reveals bidirectional mechanism of visually guided eye growth

Abstract

Myopia (nearsightedness) is the most common eye disorder, which is rapidly becoming one of the leading causes of vision loss in several parts of the world because of a recent sharp increase in prevalence. Nearwork, which produces hyperopic optical defocus on the retina, has been implicated as one of the environmental risk factors causing myopia in humans. Experimental studies have shown that hyperopic defocus imposed by negative power lenses placed in front of the eye accelerates eye growth and causes myopia, whereas myopic defocus imposed by positive lenses slows eye growth and produces a compensatory hyperopic shift in refractive state. The balance between these two optical signals is thought to regulate refractive eye development; however, the ability of the retina to recognize the sign of optical defocus and the composition of molecular signaling pathways guiding emmetropization are the subjects of intense investigation and debate. We found that the retina can readily distinguish between imposed myopic and hyperopic defocus, and identified key signaling pathways underlying retinal response to the defocus of different signs. Comparison of retinal transcriptomes in common marmosets exposed to either myopic or hyperopic defocus for 10 days or 5 weeks revealed that the primate retina responds to defocus of different signs by activation or suppression of largely distinct pathways. We also found that 29 genes differentially expressed in the marmoset retina in response to imposed defocus are localized within human myopia quantitative trait loci (QTLs), suggesting functional overlap between genes differentially expressed in the marmoset retina upon exposure to optical defocus and genes causing myopia in humans. These findings identify retinal pathways involved in the development of myopia, as well as potential new strategies for its treatment.

Atropine Differentially Modulates ECM Production by Ocular Fibroblasts, and Its Ocular Surface Toxicity Is Blunted by Colostrum

“…It is nowadays evident that myopia is strongly correlated with the axial length of the eye and not with its refractive power [18]. The growth of the eye globe is a complex event, which appears to be regulated by signals coming from the retina and the choroid, independent from the brain [19,20]. Some described chemical mediators of this signaling mechanisms are dopamine [21], TGFβ [22], and melatonin [23].…”

Analysis of genetic networks regulating refractive eye development in collaborative cross progenitor strain mice reveals new genes and pathways underlying human myopia

“…Interestingly, 27 genes that we found to be associated with refractive error development in mice were also among the genes differentially expressed in the retina of green monkeys with form-deprivation-induced myopia [39], and 233 genes were among the genes differentially expressed in the retina of marmosets exposed to positive and negative optical defocus [76]. There was also a 47-gene overlap with the genes found by Riddell et al to be differentially expressed in the retina of chicks exposed to optical defocus [77], while 292 genes found in mice overlapped with genes found to be differentially expressed in the retina of chicks with lens-induced myopia by Stone et al [78].…”

Visual Image Quality Impacts Circadian Rhythm-Related Gene Expression in Retina and in Choroid: A Potential Mechanism for Ametropias

“…Inducing ametropia in animals by altering visual input impacts a perplexing range of signaling molecules and pathways using conventional pharmacologic methods or genome-wide screens by microarray, RNA-sequencing, or other techniques. 17,48,49,59,75,76 Importantly, the circadian clock is now known to influence many and varied biological processes since the diurnal expression of 10% to 40% or more of protein coding genes overall is under diurnal control in organ-dependent patterns. 77,78 If circadian clock disruption alters the diurnal expression of a substantial number of retinal/RPE and/or choroidal genes, studying mediators downstream of clock genes could provide a framework for understanding the breadth of the signaling pathways influencing refraction, beyond just cataloging them.…”