MicroRNAs maintain visual function of photoreceptors

The maintenance of the light sensitive “antennas” of photoreceptors in the retina is important for their function. We identified microRNAs as key players in this mechanism. With this knowledge, we have been able to induce the formation of light sensitive photoreceptors in cultured retinas derived from stem cells. This opens exciting new avenues for the study of blindness and its treatment.

HFSP Long-Term Fellow Volker Busskamp and colleagues
authored on Fri, 11 July 2014

In recent years, therapeutic approaches using stem cells for retinal diseases such as age-related macular degeneration (AMD) have gained a lot of attention. However, progress has been hampered by the lack of understanding of the molecular processes controlling the maintenance of the light sensitive antennas of photoreceptors, the so-called outer segments, and the inability to grow light sensitive retinas with functional photoreceptors from stem cells.

We have now successfully identified two small RNAs, both only approximately 20 nucleotides in length, necessary for the dynamic maintenance of the outer segment of cone photoreceptors in mice. In the absence of these microRNAs, miR-182 and miR-183, cone outer segments and cone vision are lost. Cone cells are one of the two types of photoreceptors present in the retina. They are responsible for color vision and fine detail. The small miRNAs thus control the maintenance of the structures in the retina absolutely necessary for the majority of our visual tasks. In addition, the lack of microRNAs resulted in the loss of the genetic signature of these photoreceptors.

Most excitingly, miR-182 and miR-183 induced the formation of the outer segment of photoreceptors in cultured retinas derived from stem cells, and rendered these retinas light sensitive. Our findings suggest that this microRNA cluster regulates the supply of molecular components to the membranes of photoreceptors in order to control the maintenance of outer segments.

Figure: MicroRNAs maintain the light sensitive compartments of cone photoreceptors. (A) The cone photopigments (Cone Opsin, green, left panel) are expressed in the outer segments (OS) of postnatal day 60 (P60) wild type retinas (upper row). The entire cone cells are labeled in magenta (middle panel) and the three retinal nuclear layers, Outer nuclear layer (ONL), Inner nuclear layer (INL) and Ganglion cell layer (GCL), are visualized by nuclear DAPI staining (white, merged with other channels, right panel). Cone Opsin expression is almost missing in photoreceptors in which the microRNA machinery was disrupted by a cell type-specific DGCR8 knockout (C-DGCR-KO, lower row). (B) Top view of Cone Opsin-stained OS layers of wild type (upper panel) and C-DGCR-KO retinas (lower panel).(C-D) DGCR8 immunostainings of C-DGCR-KO (C) and wild type retinas (D) indicate the absence of DGCR8 in knockout retinas. Nuclear layers are visualized by DAPI staining. The upper panels show a zoomed view on the cone photoreceptor row. Scale bars, 20µm.

Reference

MiRNAs 182 and 183 are necessary to maintain adult cone photoreceptor outer segments and visual function. Busskamp V, Krol J, Nelidova D, Daum J, Szikra T, Tsuda B, Juettner F, Farrow K, Gross Scherf B, Patino Alvarez PP, Genoud C, Sothilingam V, Tanimoto N, Stadler M, Seeliger M, Stoffel M, Filipowicz W, Roska B . Neuron (2014) DOI: 10.1016/j.neuron.2014.06.020.

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