Abstract
Inherited defects in retinal photoreceptor structure impair visual transduction, disrupt relationship with the retinal pigment epithelium (RPE), and compromise cell viability. A variety of progressive retinal degenerative diseases can result, and knowledge of disease etiology remains incomplete. To investigate pathogenic mechanisms in such instances, we have characterized rod photoreceptor and retinal gene expression changes in response to a defined insult to photoreceptor structure, using the retinal degeneration slow (rds) mouse model. Global gene expression profiling was performed on flow-sorted rds and wild-type rod photoreceptors immediately prior and subsequent to times at which OSs are normally elaborated. Dysregulated genes were identified via microarray hybridization, and selected candidates were validated using quantitative PCR analyses. Both the array and qPCR data revealed that gene expression changes were generally modest and dispersed amongst a variety of known functional networks. Although genes showing major (>5-fold) differential expression were identified in a few instances, nearly all displayed transient temporal profiles, returning to WT levels by postnatal day (P) 21. These observations suggest that major defects in photoreceptor cell structure may induce early homeostatic responses, which function in a protective manner to promote cell viability. We identified a single key gene, Egr1, that was dysregulated in a sustained fashion in rds rod photoreceptors and retina. Egr1 upregulation was associated with microglial activation and migration into the outer retina at times subsequent to the major peak of photoreceptor cell death. Interestingly, this response was accompanied by neurotrophic factor upregulation. We hypothesize that activation of Egr1 and neurotrophic factors may represent a protective immune mechanism which contributes to the characteristically slow retinal degeneration of the rds mouse model.
Highlights
Human vision begins with rod and cone photoreceptors, lightsensitive ciliated sensory neurons situated in the neural retina
Identification of differentially expressed genes in rds rod photoreceptors To investigate how inherited defects in photoreceptor structure can affect cell viability, we adopted a flow-sorting method for identifying transcriptome changes in rod photoreceptors [17]. We applied this technique to the rds mouse retina, since this animal model possesses a well-defined monogenic defect in photoreceptor structure, and mutations in rds produce a broad spectrum of human retinal disease [18,19]
outer segments (OSs) of murine rod photoreceptors develop in the postnatal pup; their elaboration begins at,P10, they establish contact with the retinal pigment epithelium (RPE) by,P14, and attain their full length by,P21
Summary
Human vision begins with rod and cone photoreceptors, lightsensitive ciliated sensory neurons situated in the neural retina. These fragile cells are susceptible to a variety of insults, which can impede their function and viability and cause retinal degeneration and vision loss. A wide variety of naturally occurring and engineered mouse models have been investigated for retinal degeneration [1], and a majority of vision loss in inherited photoreceptor degenerations is known to result from secondary pathogenic processes, the detailed mechanisms by which genetic defects cause retinal degeneration continue to be debated [2,3,4,5]. It is anticipated that insights into the relatively simple monogenic diseases can simultaneously shed light on widely prevalent loss-of-sight conditions with multifactorial etiologies
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