Abstract
We used quantitative real-time PCR to examine the expression of 112 genes related to retinal function and/or belonging to known pro-apoptotic, cell survival, and autophagy pathways during photoreceptor degeneration in three early-onset canine models of human photoreceptor degeneration, rod cone dysplasia 1 (rcd1), X-linked progressive retinal atrophy 2 (xlpra2), and early retinal degeneration (erd), caused respectively, by mutations in PDE6B, RPGRORF15, and STK38L. Notably, we found that expression and timing of differentially expressed (DE) genes correlated with the cell death kinetics. Gene expression profiles of rcd1 and xlpra2 were similar; however rcd1 was more severe as demonstrated by the results of the TUNEL and ONL thickness analyses, a greater number of genes that were DE, and the identification of altered expression that occurred at earlier time points. Both diseases differed from erd, where a smaller number of genes were DE. Our studies did not highlight the potential involvement of mitochondrial or autophagy pathways, but all three diseases were accompanied by the down-regulation of photoreceptor genes, and up-regulation of several genes that belong to the TNF superfamily, the extrinsic apoptotic pathway, and pro-survival pathways. These proteins were expressed by different retinal cells, including horizontal, amacrine, ON bipolar, and Müller cells, and suggest an interplay between the dying photoreceptors and inner retinal cells. Western blot and immunohistochemistry results supported the transcriptional regulation for selected proteins. This study highlights a potential role for signaling through the extrinsic apoptotic pathway in early cell death events and suggests that retinal cells other than photoreceptors might play a primary or bystander role in the degenerative process.
Highlights
The visual process is initiated by quantal light absorption by opsin visual pigments and signal generation, first in the photoreceptor (PR) cells and subsequently through two complex synaptic pathways in the outer and inner plexiform layers to convey the information to higher visual centers
Our results indicate that in all three diseases, the majority of differentially expressed (DE) genes belong to the TNF superfamily and the extrinsic apoptotic pathway, and that several of them are produced by non-PR cells
The peak of PR cell death occurs at ~5 wks, and sustained numbers of TUNEL positive cells are present from 5-7.7 wks
Summary
The visual process is initiated by quantal light absorption by opsin visual pigments and signal generation, first in the photoreceptor (PR) cells and subsequently through two complex synaptic pathways in the outer and inner plexiform layers to convey the information to higher visual centers. The intricate structure of highly differentiated PRs is ideally suited for light absorption and signal transduction, and is highly dependent on the expression of multiple genes involved, first in PR specification, and differentiation and maintenance [1]. PR death is a common fate in retinal degenerations (reviewed by [4]) and occurs through a variety of molecular mechanisms and in response to multiple genetic or acquired insults [5]. Disease-specific cell death and survival responses depend on the underlying mutation, whether the disease occurs naturally or is induced, the speed of the degenerative process, the cell types involved, and many other factors [10,12]
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