Identifying Key Networks Linked to Light-Independent Photoreceptor Degeneration in Visual Arrestin 1 Knockout Mice

Abstract

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.