MicroRNAs: Not “Fine-Tuners” but Key Regulators of Neuronal Development and Function

Abstract

MicroRNAs (miRNAs) are a class of short non-coding RNAs that operate as prominent post-transcriptional regulators of eukaryotic gene expression. miRNAs are abundantly expressed in the brain of most animals and exert diverse roles. The anatomical and functional complexity of the brain requires the precise coordination of multilayered gene regulatory networks. The flexibility, speed, and reversibility of miRNA function provide precise temporal and spatial gene regulatory capabilities that are crucial for the correct functioning of the brain. Studies have shown that the underlying molecular mechanisms controlled by miRNAs in the nervous systems of invertebrate and vertebrate models are remarkably conserved in humans. We endeavor to provide insight into the roles of miRNAs in the nervous systems of these model organisms and discuss how such information may be used to inform regarding diseases of the human brain.

Neuronal function of the mRNA decapping complex determines survival ofCaenorhabditis elegansat high temperature through temporal regulation of heterochronic gene expression

“…miRNAs typically bind to sites in the 3′UTRs of their target mRNAs, in order to recruit the RISC complex, and thus inhibit translation and promote mRNA degradation through deadenylation, decapping and 5′–3′ decay [29]. From a functional point of view, miRNAs are either key regulators of spatio-temporal gene expression or ‘fine-tuners’ that help to provide robustness in nearly all biological processes [67], while offering a mechanism for rapid response to stress conditions [6]. Several paradigms support a model whereby miRNAs trigger the deadenylation and decay of target mRNAs during early development or in response to extracellular stimuli.…”

“…Several miRNAs, some of them evolutionarily conserved, have specific roles in neuronal development and function in C. elegans [67,79], but the extent to which the mRNA degradation machinery regulates their activity is currently unknown. Neuronal miRNA and mRNA decay mechanisms might also promote rapid stress responses and survival during environmental changes.…”

Species-Specific miRNAs in Human Brain Development and Disease

“…The Dicer enzyme cleaves pre-miRNA sequences into 21-23 nt mature miRNA double-stranded duplexes which are loaded into a pre-RISC (pre-miRNA-induced silencing complex) containing Argonaute (Ago) and other proteins. In the mature miRISC complex the ''passenger'' strand (complementary strand) is removed leaving just the ''guide'' strand (mature miRNA strand) which will bind to the mRNA target and instigate inhibition of its expression, reviewed in Winter et al (2009) and Davis et al (2015).…”

“…Of the 2,500 mature miRNAs that have been identified in humans (Friedländer et al, 2014), an estimated 70% is expressed in the nervous system (Adlakha and Saini, 2014). miRNAs have emerged as important post-transcriptional regulators of gene expression involved in neurogenesis and neural function in mammalian species (Davis et al, 2015;Nowakowski et al, 2018). A relatively small number of brain miRNAs are well characterized, including miR-92 which targets EOMES (TBR2), a T-box transcription factor that is preferentially expressed in cortical intermediate progenitors and regulates cortical neuron production and expansion, thereby affecting the thickness of the cerebral cortex (Nowakowski et al, 2013).…”

MicroRNAs as biomarkers for psychiatric disorders with a focus on autism spectrum disorder: Current progress in genetic association studies, expression profiling, and translational research

“…Expression of FOXP2 in the mouse neocortex at an abnormal time during cortical development disrupts radial migration of neurons. Abnormal expression of FOXP2 is partially repressed by endogenously expressed miR‐132 and miR‐9 in mice, attenuating the effects on neuronal radial migration [Clovis, Enard, Marinaro, Huttner, & Tonelli, ; Davis, Haas, & Pocock, ]. These studies collectively suggest that deregulation of hsa‐miR‐132 and its targets explain at least partially the pathogenesis of ASD.…”