Abstract
The pathophysiology of refractive errors is poorly understood. Myopia (nearsightedness) in particular both blurs vision and predisposes the eye to many blinding diseases during adulthood. Based on past findings of diurnal variations in the dimensions of the eyes of humans and other vertebrates, altered diurnal rhythms of these ocular dimensions with experimentally induced myopia, and evolving evidence that ambient light exposures influence refractive development, we assessed whether disturbances in circadian signals might alter the refractive development of the eye. In mice, retinal-specific knockout of the clock gene Bmal1 induces myopia and elongates the vitreous chamber, the optical compartment separating the lens and the retina. These alterations simulate common ocular findings in clinical myopia. In Drosophila melanogaster, knockouts of the clock genes cycle or period lengthen the pseudocone, the optical component of the ommatidium that separates the facet lens from the photoreceptors. Disrupting circadian signaling thus alters optical development of the eye in widely separated species. We propose that mechanisms of myopia include circadian dysregulation, a frequent occurrence in modern societies where myopia also is both highly prevalent and increasing at alarming rates. Addressing circadian dysregulation may improve understanding of the pathogenesis of refractive errors and introduce novel therapeutic approaches to ameliorate myopia development in children.
Highlights
The prevalence of myopia is high and continues to increase to alarming levels, in developed countries [1]
We find that mice with a retinal specific knockout of clock gene (Bmal1), a non-redundant component of the circadian clock [34], have myopia with a lengthened vitreous chamber, the optical compartment separating the lens and retina
We examined the refractive development of rBmal1 KO and the control mice starting at postnatal day 28 (p28) until post-natal day 70 (p70) (n = 7 rBmal1 KO; n = 10 rBmal1f//fl controls; Disrupted clock genes and ocular parameters n = 13 Chx10cre controls)
Summary
The prevalence of myopia (nearsightedness) is high and continues to increase to alarming levels, in developed countries [1]. While controversial when first proposed, myopia has been associated with early childhood exposure to ambient lighting at night [22,32], a parameter potentially disrupting the circadian clock Taken together, these reports suggest that the control of ocular refraction may be linked to circadian rhythms, which are sensitive to, and could account for, the effects of outdoor and light exposures on refractive development. Knockout of either the cycle or period gene in the circadian clock of Drosophila elongates the ommatidia pseudocones, an optical component of the fly eye that separates the facet lens and photoreceptors and insures focusing of images on photoreceptors Based on these results, we propose that the circadian clock influences the pathways that control ocular development and that expanding clinical research from light exposures per se to the broader question of the ocular effects of circadian rhythm disruptions in modern societies may well provide a useful approach to understand and to ameliorate myopia
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