Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that function as endogenous gene silencers. Soon after the discovery of miRNAs, a subset of brain-enriched and brain-specific miRNAs were identified and significant advancements were made in delineating miRNA function in brain development. However, understanding the molecular mechanisms that regulate miRNA biogenesis in normal and diseased brains has become a prevailing challenge. Besides transcriptional regulation of miRNA host genes, miRNA processing intermediates are subjected to multifaceted regulation by canonical miRNA processing enzymes, RNA binding proteins (RBPs) and epitranscriptomic modifications. Further still, miRNA activity can be regulated by the sponging activity of other non-coding RNA classes, namely circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Differential abundance of these factors in neuronal and glial lineages partly underlies the spatiotemporal expression and function of lineage-specific miRNAs. Here, we review the continuously evolving understanding of the regulation of neuronal and glial miRNA biogenesis at the transcriptional and posttranscriptional levels and the cooperativity of miRNA species in targeting key mRNAs to drive lineage-specific development. In addition, we review dysregulation of neuronal and glial miRNAs and the detrimental impacts which contribute to developmental brain disorders.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Drosha is restricted in the soma while Dicer and RNA-induced silencing complex (RISC) components are found in distal dendrites and axons [38,39], potentially allowing for spatially-restricted maturation of miRNAs
MiR-451 exerts neuroprotective effects against cerebral ischemia/reperfusion injury in stroke patients [48]. These emerging studies suggest potential roles of non-canonical miRNA-biogenesis pathways in normal and diseased brains. Another class of Dicer-independent miRNA-like molecules are derived from Argonaute-associated short introns of 80–100 nucleotides, termed agotrons, which are stabilized by AGO proteins and capable of repressing mRNAs via sequence seed-matching in the 30 -untranslated region (UTR) of the targets [49]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Emerging evidence has revealed essential roles of miRNAs in glial development and function, which can impact neurons through cell non-autonomous mechanisms via glia-neuron interactions [8,9,10]. Despite the large volume of discoveries that document the essential roles of miRNAs in brain development and function, molecular mechanisms that precisely regulate miRNA biogenesis in neuronal and glial development and impact normal and diseased brains have just begun to unfold. How distinct miRNAs converge on downstream molecular networks to advance neuronal development is a prevailing research question under active investigation. We provide an up-to-date and comprehensive review of the recent advancements and outstanding questions regarding mechanisms that control miRNA biogenesis and functional abundance in neuronal and glial lineage development, as well as how diverse neural miRNAs converge on common downstream molecular networks. We highlight recent discoveries regarding important roles of miRNAs in neuron–glia communication, malfunction of miRNAs in neurodevelopmental diseases and therapeutic potential of miRNAs in various brain disorders
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