Abstract
Photoreceptors (PRs) are specialized neuroepithelial cells of the retina responsible for sensory transduction of light stimuli. In the highly structured vertebrate retina, PRs have a highly polarized modular structure to accommodate the demanding processes of phototransduction and the visual cycle. Because of their function, PRs are exposed to continuous cellular stress. PRs are therefore under pressure to maintain their function in defiance of constant environmental perturbation, besides being part of a highly sophisticated developmental process. All this translates into the need for tightly regulated and responsive molecular mechanisms that can reinforce transcriptional programs. It is commonly accepted that regulatory non-coding RNAs (ncRNAs), and in particular microRNAs (miRNAs), are not only involved but indeed central in conferring robustness and accuracy to developmental and physiological processes. Here we integrate recent findings on the role of regulatory ncRNAs (e.g., miRNAs, lncRNAs, circular RNAs, and antisense RNAs), and of their contribution to PR pathophysiology. We also outline the therapeutic implications of translational studies that harness ncRNAs to prevent PR degeneration and promote their survival and function.
Highlights
Photoreceptors (PRs) are specialized neuronal cells adapted to the conversion of light stimuli into electrical signals
MiRNA depletion in mature rod PRs of Dicer1 conditional-knockout mice led to an early-onset severe retinal degeneration (Sundermeier et al, 2014)
Considering the well-established mutual interdependence between the retina and the retinal pigment epithelium (RPE), it is indisputable that proper miRNA expression in the latter tissue is essential for PR morphogenesis and function. This was demonstrated with the conditional deletion of Dicer1 in the developing RPE which dramatically impacted on outer segments (OS) formation and PR survival in a non-cell-autonomous manner (Ohana et al, 2015)
Summary
Photoreceptors (PRs) are specialized neuronal cells adapted to the conversion of light stimuli into electrical signals. PRs have an elevated metabolic demand due to the high rates of ion transport, opsin protein turnover, and trafficking from inner (IS) to outer segments (OS) (Figure 1A) This high energy requirement, which is almost double for a cone compared to a rod cell (Ingram et al, 2020), renders PRs vulnerable to fluctuations in energy flow. Metabolism including retinal blood flow, lipofuscin clearance, protein sorting, vesicle, and intra-flagellar transport, etc.) due to genetic changes or environmental insults can lead to PR dysfunction, cell death, and to blindness (Pearring et al, 2013) Because of their high metabolic activity, PR dysfunction is often the only phenotypic read-out of mutations in genes with ubiquitous expression, such as in the case of key ciliary genes (e.g., CEP290 and RPGR) or splicing factors (e.g., PRPF31). NcRNAs that impact PR homeostasis through ncRNAs in Photoreceptor Cells non-cell-autonomous processes (e.g., expression in other retinal cell-types or extracellular vesicles; Xu et al, 2019; Morris et al, 2020; Wooff et al, 2020) are not discussed in this mini-review
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