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.
Highlights
Enhanced short-wavelength (‘blue’) cone photoreceptors (S-cones) syndrome (ESCS) is an unusual disease of photoreceptors that includes night blindness, an abnormal electroretinogram (ERG) with a waveform that is nearly identical under both light and dark adaptation, and an increased sensitivity of the ERG to shortwavelength light [1,2]
The disease is caused by mutations in the orphan nuclear receptor transcription factor NR2E3, which is expressed exclusively in rods [3,4]
In this paper we have determined that the primary role of the rod-specific transcription factor, Nr2e3, is to maintain cone genes transcriptionally silent within rods
Summary
Enhanced S-cone syndrome (ESCS) is an unusual disease of photoreceptors that includes night blindness (suggestive of rod dysfunction), an abnormal electroretinogram (ERG) with a waveform that is nearly identical under both light and dark adaptation, and an increased sensitivity of the ERG to shortwavelength light [1,2]. Histopathologic analysis of a retina from a human patient with ESCS and extensive retinal degeneration demonstrated an absence of rhodopsin-positive cells and an increase in the number of S-cone opsin-expressing cells. In addition to the ERG findings, patients with ESCS have dysmorphic retinas with rosette formation in the outer nuclear layer (ONL) where photoreceptor cell bodies reside, and a slow retinal degeneration that can lead to complete blindness [12,13,14]
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