title: Defective photoreceptor phagocytosis in a mouse model of enhanced S-cone syndrome causes progressive retinal degeneration.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4965, USA. kxp65@case.edu
authors.forename: Debarshi
authors.initials: D
authors.lastname: Mustafi
authors.forename: Brian M
authors.initials: BM
authors.lastname: Kevany
authors.forename: Christel
authors.initials: C
authors.lastname: Genoud
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Okano
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Andreas
authors.initials: A
authors.lastname: Engel
authors.forename: Mark D
authors.initials: MD
authors.lastname: Adams
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000209:etiology* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; C084884:Nrl protein, mouse