Abstract
Retinitis pigmentosa (RP) is a generic term for a group of genetic diseases characterized by loss of rod and cone photoreceptor cells. Although the genetic causes of RP frequently only affect the rod photoreceptor cells, cone photoreceptors become stressed in the absence of rods and undergo a secondary degeneration. Changes in the gene expression profile of cone photoreceptor cells are likely to occur prior to observable physiological changes. To this end, we sought to achieve greater understanding of the changes in cone photoreceptor cells early in the degeneration process of the Rho−/− mouse model. To account for gene expression changes attributed to loss of cone photoreceptor cells, we normalized PCR in the remaining number of cones to a cone cell reporter (OPN1-GFP). Gene expression profiles of key components involved in the cone phototransduction cascade were correlated with tests of retinal cone function prior to cell loss. A significant downregulation of the photoreceptor transcription factor Crx was observed, which preceded a significant downregulation in cone opsin transcripts that coincided with declining cone function. Our data add to the growing understanding of molecular changes that occur prior to cone dysfunction in a model of rod-cone dystrophy. It is of interest that gene supplementation of CRX by adeno-associated viral vector delivery prior to cone cell loss did not prevent cone photoreceptor degeneration in this mouse model.
Highlights
Retinitis pigmentosa (RP) is an incurable inherited retinal disease (IRD) that affects approximately 1 in 4000 people [1] and it most commonly arises from genetic mutations in genes specific to rod photoreceptor cells
To provide an understanding of the changes in the expression profile over time for genes involved in the cone phototransduction cascade, tissue samples were collected from age-matched Rho−/−OPN1-GFP mice and wild-type OPN1-GFP mice
By characterizing the progression of changes in cone function in Rho−/−OPN1-GFP mouse model, we identified that a downregulation in expression of Crx preceded structural and functional changes in cone photoreceptor cells
Summary
Retinitis pigmentosa (RP) is an incurable inherited retinal disease (IRD) that affects approximately 1 in 4000 people [1] and it most commonly arises from genetic mutations in genes specific to rod photoreceptor cells. A common intervention approach to preserve cone cell function and prevent cone cell apoptosis would be valuable—a “mutation-independent” strategy Such a broad treatment could be more widely applied than a narrow therapy targeting only a single mutant variant of RP. This report identifies significant downregulation of the genes Crx and Opn1sw relative to OPN1-GFP expression levels in the Rho−/− mouse model These changes occurred prior to detectable changes in cone function and survival. Since Crx acts upstream of Opn, we tested the hypothesis that reversing Crx downregulation might delay cone cell death when occurring secondary to rod loss in the Rho−/− mouse model. This did not prevent cone cell degeneration, implying that downregulation of cone-specific genes such as Crx may be a global secondary effect of cone stress rather than being primary drivers of cone cell degeneration
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