PMID- 37287644 OWN - NLM STAT- MEDLINE DCOM- 20230609 LR - 20231115 IS - 1090-0535 (Electronic) IS - 1090-0535 (Linking) VI - 29 DP - 2023 TI - Encephalopsin (OPN3) is required for normal refractive development and the GO/GROW response to induced myopia. PG - 39-57 AB - PURPOSE: Myopia, or nearsightedness, is the most common form of refractive error and is increasing in prevalence. While significant efforts have been made to identify genetic variants that predispose individuals to myopia, these variants are believed to account for only a small portion of the myopia prevalence, leading to a feedback theory of emmetropization, which depends on the active perception of environmental visual cues. Consequently, there has been renewed interest in studying myopia in the context of light perception, beginning with the opsin family of G-protein coupled receptors (GPCRs). Refractive phenotypes have been characterized in every opsin signaling pathway studied, leaving only Opsin 3 (OPN3), the most widely expressed and blue-light sensing noncanonical opsin, to be investigated for function in the eye and refraction. METHODS: Opn3 expression was assessed in various ocular tissues using an Opn3eGFP reporter. Weekly refractive development in Opn3 retinal and germline mutants from 3 to 9 weeks of age was measured using an infrared photorefractor and spectral domain optical coherence tomography (SD-OCT). Susceptibility to lens-induced myopia was then assessed using skull-mounted goggles with a -30 diopter experimental and a 0 diopter control lens. Mouse eye biometry was similarly tracked from 3 to 6 weeks. A myopia gene expression signature was assessed 24 h after lens induction for germline mutants to further assess myopia-induced changes. RESULTS: Opn3 was found to be expressed in a subset of retinal ganglion cells and a limited number of choroidal cells. Based on an assessment of Opn3 mutants, the OPN3 germline, but not retina conditional Opn3 knockout, exhibits a refractive myopia phenotype, which manifests in decreased lens thickness, shallower aqueous compartment depth, and shorter axial length, atypical of traditional axial myopias. Despite the short axial length, Opn3 null eyes demonstrate normal axial elongation in response to myopia induction and mild changes in choroidal thinning and myopic shift, suggesting that susceptibility to lens-induced myopia is largely unchanged. Additionally, the Opn3 null retinal gene expression signature in response to induced myopia after 24 h is distinct, with opposing Ctgf, Cx43, and Egr1 polarity compared to controls. CONCLUSIONS: The data suggest that an OPN3 expression domain outside the retina can control lens shape and thus the refractive performance of the eye. Prior to this study, the role of Opn3 in the eye had not been investigated. This work adds OPN3 to the list of opsin family GPCRs that are implicated in emmetropization and myopia. Further, the work to exclude retinal OPN3 as the contributing domain in this refractive phenotype is unique and suggests a distinct mechanism when compared to other opsins. CI - Copyright (c) 2023 Molecular Vision. FAU - Linne, Courtney AU - Linne C AD - Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Science of Light Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Molecular & Developmental Biology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, OH. AD - Medical Scientist Training Program, University of Cincinnati, College of Medicine, Cincinnati, OH. FAU - Mon, Khine Yin AU - Mon KY AD - Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Science of Light Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. FAU - D'Souza, Shane AU - D'Souza S AD - Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Science of Light Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Molecular & Developmental Biology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, OH. FAU - Jeong, Heonuk AU - Jeong H AD - Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan. AD - Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan. FAU - Jiang, Xiaoyan AU - Jiang X AD - Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan. AD - Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan. FAU - Brown, Dillon M AU - Brown DM AD - Department of Ophthalmology and Neuroscience Program, Emory University School of Medicine, Atlanta, GA. AD - Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, GA. FAU - Zhang, Kevin AU - Zhang K AD - Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Science of Light Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Molecular & Developmental Biology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, OH. AD - Medical Scientist Training Program, University of Cincinnati, College of Medicine, Cincinnati, OH. FAU - Vemaraju, Shruti AU - Vemaraju S AD - Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Science of Light Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH. FAU - Tsubota, Kazuo AU - Tsubota K AD - Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan. AD - Tsubota Laboratory, Inc., Tokyo, Japan. FAU - Kurihara, Toshihide AU - Kurihara T AD - Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan. AD - Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan. FAU - Pardue, Machelle T AU - Pardue MT AD - Department of Ophthalmology and Neuroscience Program, Emory University School of Medicine, Atlanta, GA. AD - Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Health Care System, Decatur, GA. FAU - Lang, Richard A AU - Lang RA AD - Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Science of Light Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. AD - Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH. LA - eng GR - IK6 RX003134/RX/RRD VA/United States GR - R01 EY016435/EY/NEI NIH HHS/United States GR - R01 EY032566/EY/NEI NIH HHS/United States GR - R01 EY032029/EY/NEI NIH HHS/United States GR - T32 GM063483/GM/NIGMS NIH HHS/United States GR - R01 EY032752/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230514 PL - United States TA - Mol Vis JT - Molecular vision JID - 9605351 RN - 0 (Opsins) RN - 0 (OPN3 protein, mouse) RN - 0 (Rod Opsins) SB - IM MH - Animals MH - Mice MH - *Myopia/genetics MH - Refraction, Ocular MH - *Refractive Errors MH - Retina MH - Opsins/genetics MH - Rod Opsins PMC - PMC10243678 EDAT- 2023/06/08 06:42 MHDA- 2023/06/09 06:42 PMCR- 2023/01/01 CRDT- 2023/06/08 04:21 PHST- 2023/03/13 00:00 [received] PHST- 2023/05/05 00:00 [accepted] PHST- 2023/06/09 06:42 [medline] PHST- 2023/06/08 06:42 [pubmed] PHST- 2023/06/08 04:21 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 5 [pii] PST - epublish SO - Mol Vis. 2023 May 14;29:39-57. eCollection 2023.