The ipRGC-Dopamine-EGR1 Axis in Myopia: A Mechanistic Hypothesis Linking Near-Work, Convergence Miosis and Retinal Photoreception

Abstract

Myopia is now one of the most common visual disorders in the world, and its prevalence continues to rise at a pace that genetics alone cannot easily explain. Near work and reduced time outdoors are well-established environmental risk factors, but the chain of molecular events that converts these everyday exposures into pathological axial elongation is still only partly understood. This review sets out a mechanistic hypothesis built around three retinal elements that, considered together, may help close that gap: intrinsically photosensitive retinal ganglion cells (ipRGCs), the dopaminergic amacrine cell network of the retina, and the transcription factor early growth response 1 (EGR1). The central proposal is that sustained near work brings about convergence-driven pupillary miosis, which lowers retinal illuminance and selectively dampens the light response of melanopsin-expressing ipRGCs. Because these cells normally drive dopamine release from retinal amacrine cells, their reduced activity is expected to lower retinal dopamine synthesis and tonic release, which in turn relieves the dopaminergic brake on EGR1 transcription. The resulting rise in EGR1 in the retina and sclera is proposed to alter gene networks governing scleral extracellular matrix turnover, favouring progressive axial elongation. Taken together, this axis links photoreceptive, neurochemical, and transcriptional events into a single explanatory framework, one that fits comfortably with several long-standing observations: the protective effect of bright outdoor light, the apparent benefit of certain short-wavelength light exposures, and the retinal pharmacology underlying atropine's effect on myopia progression. Evidence drawn from transgenic animals, pharmacological studies, and a small but growing body of clinical work lends support to each step of the proposed cascade, although the support is, at this stage, convergent rather than conclusive. A critical reading of the literature also exposes important gaps, the most pressing being the lack of any direct human evidence that convergence miosis meaningfully reduces ipRGC irradiance responses during ordinary near work. The review closes by identifying the experimental and clinical work most likely to confirm, refine, or overturn this hypothesis.