Mouse NR2E3R296Q Mutation Disrupts Photoreceptor Developmental Paradigm and Leads to Early-Onset Progressive Retinal Degeneration by Suppressing RXRG Signaling.

The NR2E3R311Q mutation can lead to retinitis pigmentosa, enhanced S-cone syndrome (ESCS), Goldmann-Favre syndrome, and clumped pigmentary retinal degeneration. The relationship between this mutation and various recessive inherited retinal degenerative disorders is unclear and complicates clinical diagnosis and treatment. In this study, we generated a mouse strain carrying the NR2E3R296Q mutation using CRISPR/Cas9 technology to simulate the NR2E3R311Q mutation in humans and investigate the influence of this missense mutation on the photoreceptor developmental profile and retinal maintenance. Retinal architecture and lamination were normal in NR2E3R296Q mice. Whorls and rosettes were not observed in the outer nuclear layer (ONL). Rod cell quantity developed normally, whereas a small amount of Rhodopsin was incorrectly located in the ONL. Blue cones were excessively produced at the dorsal retina, whereas green cone development was normal. Colocalization of Rhodopsin and Arrestin occurred in the retinas of NR2E3R296Q mice. Heterozygous NR2E3+/R296Q mice showed no evident abnormalities in retinal structure or photoreceptor development. Retinas of NR2E3R296Q mice underwent progressive degeneration starting in the early postnatal stage, which manifested as reduced ONL thickness and outer segment fragmentation. The dorsal retina, where redundant blue cones are generated, degenerated in a more advanced manner. At the molecular level, NR2E3 bound directly to the RXRG promoter, whereas the NR2E3 R296Q mutation significantly impaired binding, resulting in significantly decreased RXRG mRNA and protein expressions. In summary, we developed a novel mouse model exhibiting an ESCS-like phenotype, thus providing a novel NR2E3-RXRG signaling pathway for modulating photoreceptor development and retinal maintenance.