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

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.

NR2E3mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP)

“…A derepression of additional cone-specific genes, e.g., cone transducin (Gnat2), cone phosphodiesterases (Pde6c, Pde6h) cone arrestin (Arr3), but not M-opsin (Opn1mw), probably occurs in these cells from P14 on, in accordance with the reported in vitro repressor function of NR2E3 [Chen et al, 1999Corbo and Cepko, 2005;Haider et al, in press;Kobayashi et al, 1999]. However, a majority of photoreceptors represent a morphologically hybrid cell type expressing both rod and cone genes, providing circumstantial evidence that NR2E3 is essential to suppress cone-specific gene expression in mature rods Cheng et al, 2004;Corbo and Cepko, 2005;Peng et al, 2005]. Cone-specific gene expression is also suppressed in transgenic mice ectopically expressing NR2E3 under the control of the Crx promoter in photoreceptor precursor cells; instead of cones, nonfunctional rod-like photoreceptors are generated [Cheng et al, 2006].…”

“…In the absence of NR2E3, an about two-fold increase in short wavelength-sensitive (S)-opsin (Opn1sw) expressing cones (''blue'' cones) is observed, indicating that NR2E3 acts as a suppressor of the cone generation program in late mitotic retinal progenitor cells [Haider et al, 2001[Haider et al, , 2006. A derepression of additional cone-specific genes, e.g., cone transducin (Gnat2), cone phosphodiesterases (Pde6c, Pde6h) cone arrestin (Arr3), but not M-opsin (Opn1mw), probably occurs in these cells from P14 on, in accordance with the reported in vitro repressor function of NR2E3 [Chen et al, 1999Corbo and Cepko, 2005;Haider et al, in press;Kobayashi et al, 1999]. However, a majority of photoreceptors represent a morphologically hybrid cell type expressing both rod and cone genes, providing circumstantial evidence that NR2E3 is essential to suppress cone-specific gene expression in mature rods Cheng et al, 2004;Corbo and Cepko, 2005;Peng et al, 2005].…”

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

“…b) Morphological and microarray analysis of the rd7 retina indicate that the majority of photoreceptors exhibit a hybrid rod-cone phenotype, i.e. expressing both rod and cone genes Corbo and Cepko, 2005). c) Direct target gene studies suggest that Nr2e3 is a dual transcription regulator for both rod and cone genes.…”

Neurogenesis in the Fish Retina

“…PNR transcriptionally activates rod-specific genes, and in mice and humans lacking PNR activity, S-opsin expression is enhanced and this expression takes place in morphologically hybrid photoreceptors (Corbo and Cepko, 2005). Surprisingly little information is available from the teleost fish models regarding the role of nuclear hormone receptors, with the exception of the recent identification of the zebrafish PNR gene and its transient expression in cones, followed by persistent expression in rods .…”