Abstract
Purpose :
In last decade, the microRNAs (miRNAs) are emerging as key players in the control of fundamental biological processes in both physiological and pathological conditions. Recently miR-204 and miR-211 were identified as key regulators of lysosomal biogenesis and function in the RPE/photoreceptor crosstalk. Notably, mutation in miR-204 was responsible for an autosomal dominant inherited retinal dystrophy associated to coloboma. Furthermore, recent genomic and genetic studies for AMD risk identified miR-211 as possible causal gene for AMD. Depletion of miR-211 in mice fully resembles AMD phenotype associated to autophagy impairments. Despite this notion, the relationship occurring between their function and RPE/retina crosstalk is yet not fully addressed. To gain insights in this direction, here, we focus on the in vivo role of both miR-204 and miR-211, in both mammalian and teleost models.
Methods :
To define the contribution of miR-204 and miR-211 in the RPE/retina crosstalk, we generated and investigated the RPE/retina in miR-204-/- and miR-211-/- rodent, medaka fish and human RPE cell models. We performed transcriptomic, proteomic, Western blot, immunofluorescence, and transmission electron microscopy analyses on in vivo and in vitro models. Both gene therapy and pharmacological treatment was used to validate the miR-204/211 molecular network. We also evaluated the therapeutic use of miR-211 and pharmacological repression of its targets as a mutation-independent strategy to rescue retinal dystrophies associated to accumulation of unfolded retinal protein (i.e. RHO-P23H mice).
Results :
We found that deletion of miR-204 and miR-211 in mouse and medaka fish, respectively, resulted in a deleterious cell clearance program associated to a progressive retinal degeneration characterized by an impaired electroretinogram (ERG) response to light stimuli. Furthermore, our data clearly demonstrate the therapeutic use of miR-211 and the repression of its target to induce cell clearance and to rescue retinal degeneration in RHO-P23H mice.
Conclusions :
Taken together, our results gain a comprehensive understanding of miR-204/211 function and dysfunction but also established the existence of precise network between miR-204/211 function and the RPE/photoreceptor crosstalk opening new perspective for the use of this knowledge to develop novel therapeutic strategies to treat inherited retinal dystrophies.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.