Defective photoreceptor phagocytosis in a mouse model of enhanced S-cone syndrome causes progressive retinal degeneration

Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4965, USA.
The FASEB Journal (Impact Factor: 5.04). 06/2011; 25(9):3157-76. DOI: 10.1096/fj.11-186767
Source: PubMed


Enhanced S-cone syndrome (ESCS), featuring an excess number of S cones, manifests as a progressive retinal degeneration that leads to blindness. Here, through optical imaging, we identified an abnormal interface between photoreceptors and the retinal pigment epithelium (RPE) in 9 patients with ESCS. The neural retina leucine zipper transcription factor-knockout (Nrl(-/-)) mouse model demonstrates many phenotypic features of human ESCS, including unstable S-cone-positive photoreceptors. Using massively parallel RNA sequencing, we identified 6203 differentially expressed transcripts between wild-type (Wt) and Nrl(-/-) mouse retinas, with 6 highly significant differentially expressed genes of the Pax, Notch, and Wnt canonical pathways. Changes were also obvious in expression of 30 genes involved in the visual cycle and 3 key genes in photoreceptor phagocytosis. Novel high-resolution (100 nm) imaging and reconstruction of Nrl(-/-) retinas revealed an abnormal packing of photoreceptors that contributed to buildup of photoreceptor deposits. Furthermore, lack of phagosomes in the RPE layer of Nrl(-/-) retina revealed impairment in phagocytosis. Cultured RPE cells from Wt and Nrl(-/-) mice illustrated that the phagocytotic defect was attributable to the aberrant interface between ESCS photoreceptors and the RPE. Overcoming the retinal phagocytosis defect could arrest the progressive degenerative component of this disease.

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    • "Granular spots with weak fluorescence were detected in both 6–week–old and 6–month–old Nrl −/− and Nrl −/− Rdh8 −/− Abca4 −/− mice, and a mild increase of AF intensity was observed with increasing age (Fig. S4A right and B). This observation is consistent with aberrant phagocytosis and transport of A2E to the RPE by these mice (Mustafi et al. 2011). However, amounts of A2E in the eye were significantly increased at 4 and 6 months of age in mice lacking Abca4 and Rdh8. "
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