A Hybrid Photoreceptor Expressing Both Rod and Cone Genes in a Mouse Model of Enhanced S-Cone Syndrome

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Abstract
Rod and cone photoreceptors subserve vision under dim and bright light conditions, respectively. The differences in their function are thought to stem from their different gene expression patterns, morphologies, and synaptic connectivities. In this study, we have examined the photoreceptor cells of the retinal degeneration 7 (rd7) mutant mouse, a model for the human enhanced S-cone syndrome (ESCS). This mutant carries a spontaneous deletion in the mouse ortholog of NR2E3, an orphan nuclear receptor transcription factor mutated in ESCS. Employing microarray and in situ hybridization analysis we have found that the rd7 retina contains a modestly increased number of S-opsin–expressing cells that ultrastructurally appear to be normal cones. Strikingly, the majority of the photoreceptors in the rd7 retina represent a morphologically hybrid cell type that expresses both rod- and cone-specific genes. In addition, in situ hybridization screening of genes shown to be up-regulated in the rd7 mutant retina by microarray identified ten new cone-specific or cone-enriched genes with a wide range of biochemical functions, including two genes specifically involved in glucose/glycogen metabolism. We suggest that the abnormal electroretinograms, slow retinal degeneration, and retinal dysmorphology seen in humans with ESCS may, in part, be attributable to the aberrant function of a hybrid photoreceptor cell type similar to that identified in this study. The functional diversity of the novel cone-specific genes identified here indicates molecular differences between rods and cones extending far beyond those previously discovered. Vision begins with light entering the eye. This light is projected onto the retina, a thin neural structure lining the inside of the eye. Photoreceptors, among the most important cell types in the retina, are the first to receive the incoming rays of light. In mammals, there are two types of photoreceptors: rods and cones. Rods are specialized for nighttime vision, and cones for daytime and color vision. In this study, the authors examined the photoreceptors of a mouse with a gene mutation that causes photoreceptors to develop abnormally. Humans with a similar mutation have a form of blindness called enhanced S-cone syndrome (ESCS). Surprisingly, the majority of photoreceptors in this mutant mouse were found to have features of both normal rods and cones. It is possible that the abnormal features of these photoreceptors predispose them to undergo premature death. If this model accurately reflects the situation in human patients with ESCS, it may provide an explanation for the loss of vision seen in this disease. This study also elucidated previously unknown molecular differences between normal rods and cones. This new knowledge may contribute to a better overall understanding of the mechanisms underlying night, day, and color vision.