Abstract
Brain regions, such as the cortex and retina, are composed of layers of uniform thickness. The molecular mechanism that controls this uniformity is not well understood. Here we show that during mouse postnatal development the timed expression of Rncr4, a retina-specific long noncoding RNA, regulates the similarly timed processing of pri-miR-183/96/182, which is repressed at an earlier developmental stage by RNA helicase Ddx3x. Shifting the timing of mature miR-183/96/182 accumulation or interfering with Ddx3x expression leads to the disorganization of retinal architecture, with the photoreceptor layer being most affected. We identify Crb1, a component of the adhesion belt between glial and photoreceptor cells, as a link between Rncr4-regulated miRNA metabolism and uniform retina layering. Our results suggest that the precise timing of glia–neuron interaction controlled by noncoding RNAs and Ddx3x is important for the even distribution of cells across layers.
Highlights
Brain regions, such as the cortex and retina, are composed of layers of uniform thickness
We found that premature accumulation of miR-183/96/182 processed from Truncated pri-miR-183/96/182 version 2 (T2)-pri-miR-183/96/182 resulted in a phenotype similar to that seen in the early knockdown of Ddx3x, with retinas at P10 and later having a wavy form with pronounced folds in the photoreceptor layer, as well as large regional variation in thickness (Fig. 5c,d and Supplementary Fig. 5d,e)
We have described a regulatory network consisting of long noncoding RNAs (lncRNAs) Rncr[4], RNA helicase Ddx3x and miR-183/96/182 that controls the timing of miR-183/96/182 accumulation in photoreceptors
Summary
Brain regions, such as the cortex and retina, are composed of layers of uniform thickness. Different classes of non-protein-coding RNAs, including long noncoding RNAs (lncRNAs; 4200 nucleotides) or microRNAs (miRNAs; B21-nucleotide long), are dynamically expressed in eukaryotes in a developmental-, tissue- or cell type-specific manner and control diverse biological processes. Knockdown or aberrantly timed expression of mouse Miat ( known as Rncr2—retinal noncoding RNA 2), Six3os[1], Tug[1] or Vax2os lncRNAs results in improper differentiation of photoreceptor progenitor cells and defects in cell type specification[12,13,14,15]. Depletion of all or particular miRNAs in developing mouse retina leads to aberrant photoreceptor layer architecture[26], improper cell specification[27], progressive photoreceptor degeneration[26,28,29], functional defects[28] or cell death[30]. MiR-182 and miR-183 are important in the maintenance of cone outer segments and cone function in adult mice[33]
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