The role of retinoic acid signaling in myopia
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Jonnalagadda, Aparna
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Abstract
Retinoic acid (RA) signaling has been linked to myopia, but results across species are inconsistent: some studies suggest the choroid produces all-trans retinoic acid (atRA), yet our previous work shows that only retinal atRA changes in response to myopic stimuli and light. How RA signaling adapts to these stimuli—and how these changes influence the sclera—remains unclear. Because atRA activity is due to a complex and spatially dependent balance between atRA synthesis and degradation, mapping this landscape may reveal mechanisms of myopigenesis. We examined RA signaling after myopia induction or pharmacological manipulation. Natural refractive variability was assessed in 2nd-generation mice from a C57BL/6J×129S2/SvPasCrl cross (n=12 animals). To evaluate signaling during myopia induction and recovery, we analyzed eyes after 1 week of form-deprivation myopia (FDM n=4; naïve n=2) and after 24 hrs of recovery from FDM (n=2). To directly manipulate RA signaling, mice received atRA (n=15; control n=6) or the atRA-synthesis inhibitor WIN18,446 (WIN n=3; WIN+FDM n=4; control n=6) via feeding or IP injection, respectively. Eyes were collected and processed for immunofluorescence using antibodies against atRA-synthesizing enzymes (RALDH1, RALDH2) and the atRA-degrading enzyme CYP26A1. Hoechst and anti-vimentin were used as counterstains. Expression was also confirmed using publicly available single-cell RNA-seq datasets. Cell types expressing RA-related enzymes were consistent across all conditions. In the retina, RALDH1 was mainly restricted to Müller glia in the superior hemisphere, and was present throughout the RPE, choroid, and scleral fibroblasts in both hemispheres. RALDH2 appeared absent in the eye. CYP26A1 is localized to cells in the retinal ganglion cell (RGC) layer, horizontal cells, photoreceptor connecting cilia, a subset of RPE cells, and broadly across the choroid. Based on enzyme expression, inner-retinal atRA synthesis is primarily driven by Müller glia. CYP26 expression in RGC layer cells and horizontal cells suggests that local degradation likely limits the non-cell-autonomous effects of atRA. RALDH1 is widespread in the choroid and sclera, while CYP26 is broadly expressed only in the choroid. These will help understand how atRA influences the sclera during environmentally driven eye growth, and to establish the functional importance of scleral versus retinal-derived atRA.
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2026-05
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Undergraduate Thesis