MicroRNAs in neuronal function and dysfunction

Abstract

MicroRNAs (miRNAs) are small noncoding RNA transcripts expressed throughout the brain that can regulate neuronal gene expression at the post-transcriptional level. Here, we provide an overview of the role for miRNAs in brain development and function, and review evidence suggesting that dysfunction in miRNA signaling contributes to neurodevelopment disorders such as Rett and fragile X syndromes, as well as complex behavioral disorders including schizophrenia, depression and drug addiction. A better understanding of how miRNAs influence the development of neuropsychiatric disorders may reveal fundamental insights into the causes of these devastating illnesses and offer novel targets for therapeutic development.

Figure 1

MicroRNA biogenesis and function. (1) MicroRNA (miRNA) genes are transcribed by RNA polymerase II or III to generate primary miRNA (pri-miRNA) transcripts, which form a hairpin secondary structure 50–120 nt in length. (2) Pri-miRNAs are cleaved by a multiprotein complex that includes Drosha and DiGeorge syndrome critical region gene 8 (DCRC8), also known as Pasha. This cleavage event yields the pre-miRNA, which is exported from the nucleus to the cytoplasm by Exportin-5. (3) In the cytoplasm, Dicer cleaves the hairpin loop to generate a miRNA duplex, which is then unwound to yield a ~22 nt single-stranded mature miRNA from one arm of the pre-miRNA (4). (5) The mature miRNA is incorporated into the RNA-induced silencing complex (RISC) in a carefully orchestrated sequence of events regulated by Dicer, TAR RNA-binding protein (TRBP), the Argonaute proteins including Ago2, and other regulatory proteins such as GW182 [also known as trinucleotide repeat containing 6A (TNRC6A)] and fragile X mental retardation protein (FMRP) (6) Once incorporated into RISC, the miRNA guides this ribonucleoprotein complex to specific mRNA transcripts through complementary base-pairing interactions with regions in the 3′UTR of the target mRNA transcript, termed miRNA response elements (MREs).

Figure 2

MicroRNA regulation of dendritic spine formation and maturation. MicroRNAs (miRNAs) interact with transcription factors, deacetylases and kinases, growth factors and other components of intracellular machinery known to regulate dendritic spine formation and/or maturation, and thereby influence dendritic morphology. Some of the known interactions between miRNAs and regulators of dendritic morphology in vitro and in vivo are illustrated here. For the sake of clarity, not all interconnections between these miRNAs and target genes are shown; see text for details. Green lines indicate a stimulatory effect and red lines indicate an inhibitory effect. Abbreviations: APT1, acyl protein thioesterase; BDNF, brain-derived neurotrophic factor; CREB, cAMP response binding protein; LimK1, LIM domain kinase 1; MeCP2, methyl CpG binding protein 2; PAK, p21 protein activated kinase; RAC1, Ras-related C3 botulinum toxin substrate 1; Sirt1, sirtuin 1.

Figure 3

Developing microRNA-based therapeutics. (a) The left panel shows an RNA monomer, and the right panel shows an LNA-modified oligonucleotide monomer in the locked 3′-endo conformation of the furanose ring. LNA-modified antisense oligonucleotides against targeted miRNAs are currently in Phase II clinical trials for hepatitis C virus (clinical trial identifier NCT01200420; http://www.clinicaltrials.gov). (b) Exosomes targeted to the brain, achieved by tethering the exosome-expressed protein Lamp2b (lysosome-associated membrane protein-2) with rabies virus glycoprotein (RVG), represent a potential mechanism to deliver miRNA mimetic or antisense oligonucleotide cargos selectively to the brain (e.g. [101]). (c) A screening strategy used successfully to identify novel small-molecule activators and inhibitors of discrete miRNAs [102,103]. The miRNA response element (MRE) sequence for a given miRNA is cloned downstream of the luciferase gene. Increases in the activity of a miRNA that binds to the MRE results in lower luciferase activity, reflected in diminished luminescence, whereas decreased activity results in increased luminescence.