Identifying Key Networks Linked to Light-Independent Photoreceptor Degeneration in Visual Arrestin 1 Knockout Mice
When visual arrestin 1 (ARR1, S-antigen, 48 KDa protein) was genetically knocked out in mice (original Arr1 −/− , designated Arr1 −/−A ), rod photoreceptors degenerated in a light-dependent manner. Subsequently, a light-independent cone dystrophy was identified with minimal rod death in ARR1 knockout mice (Arr1 −/−A Arr4+/+, designated Arr1 −/−B ), which were F2 littermates from breeding the original Arr1 −/−A and cone arrestin knockout 4 (Arr4 −/− ) mice. To resolve the genetic and phenotypic differences between the two ARR1 knockouts, we performed Affymetrix™ exon array analysis to focus on the potential differential gene expression profile and to explore the molecular and cellular pathways leading to this observed susceptibility to cone dystrophy in Arr1 −/−B compared to Arr1 −/−A or control Arr1 +/+ Arr4 +/+ (wild type [WT]). Only in the Arr1 −/−B retina did we observe an up-regulation of retinal transcripts involved in the immune response, inflammatory response and JAK-STAT signaling molecules, OSMRβ and phosphorylation of STAT3. Of these responses, the complement system was significantly higher, and a variety of inflammatory responses by complement regulation and anti-inflammatory cytokine or factors were identified in Arr1 −/−B retinal transcripts. This discovery supports that Arr1 −/−B has a distinct genetic background from Arr1 −/−A that results in alterations in its retinal phenotype leading to susceptibility to cone degeneration induced by inappropriate inflammatory and immune responses.
KeywordsCone dystrophy Visual arrestin 1 Genetic susceptibility Retinitis pigmentosa
We thank Andrew Vargus and other members in the USC Rocki Eye Institute Laboratory in Vision Research for technical support with data analysis, Neena Haider (Schepens Eye Research Institute, Harvard) for scientific discussions, Jeannie Chen for providing Arr1 −/−A mice, and the Children’s Hospital Los Angeles Microarray Core Facility and USC NML Bioinformatics Service for technical support. Grant support, in part, from NEI EY015851 and core grants: EY03040, Research to Prevent Blindness (USC Ophthalmology), and the M. D. Allen Foundation.
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