microRNAs in neurons: manifold regulatory roles at the synapse
Highlights
► miRNAs are particularly plentiful in neurons, where they fulfill important roles in the development and plasticity of neural circuits. ► A subset of synaptic microRNAs controls the morphogenesis of dendrites and spines by regulating the local synthesis of important synaptic proteins. ► microRNA expression and function itself is subject to a plethora of activity-dependent regulatory mechanisms. ► First examples of a physiological role of microRNAs in learning and memory in both invertebrate and vertebrate model organisms are emerging. ► Deregulated microRNA expression might contribute to neurodevelopmental and neuropsychiatric disorders, thereby representing a novel target for therapeutic intervention.
Introduction
MiRNAs are approximately 19–23 nucleotides in length and act as key molecules in sequence-specific post-transcriptional gene regulation [1]. They derive from long primary transcripts (pri-miRNAs), which are cleaved to ∼70 nt stemloop precursors (pre-miRNAs) and then further processed in the cytoplasm by the RNaseIII Dicer to mature miRNAs. MiRNAs are loaded into a multi-protein complex, the so-called RNA induced silencing complex (RISC), which then targets the 3′UTR of mRNAs with partial complementarity for the miRNA. The presence of miRNA associated RISC (miRISC) at the 3′UTR usually reduces protein synthesis from the cognate transcript, by translational repression and/or through destabilization of the targeted mRNA. Given that at least half of the cellular proteome is under miRNA control, it can be surmised that miRNAs fulfill critical regulatory functions in virtually every cellular process. Similar to transcription factors, many miRNAs are expressed in a developmental-stage and tissue-specific manner. Interestingly, miRNAs are especially abundant in the central nervous system, suggesting that they might be particularly important there. The knockdown of Dicer demonstrated that a functional neuronal miRNA system is absolutely crucial for both the correct development of the nervous system as a whole and for the differentiation, proper function and survival of individual neurons [2, 3, 4, 5, 6, 7, 8, 9]. In this review, we will focus on recent advances in the neuronal miRNA field with regard to synapse development, plasticity and pathology.
Section snippets
miRNAs in synapse development and physiology
Synapses are dynamic structures whose strength is regulated by the activity of their respective neuronal circuits. The underlying adaptive processes can include changes in the quantity of neurotransmitter release, alterations to the number of neurotransmitter receptors, and changes in synapse morphology caused by reorganization of the actin cytoskeleton. In our current understanding this plasticity of the synapse is an important cellular substrate for higher cognitive functions like learning
Evidence for the role of miRNAs in synapse dysfunction
Perturbations in the morphology and/or quantity of dendritic spines can negatively alter synaptic plasticity and contribute to a vast number of neuropathological conditions. Ultimately, this can encroach on the ability of an individual to process information in a coherent and logical manner. Perhaps, the neurological condition for which a causative role for miRNAs has been most convincingly demonstrated is schizophrenia (SZ). One study in particular has shown a genetic association between
Conclusion
Recent research has unveiled the existence of a complex network of synaptic miRNAs. To date, only a subset of these miRNAs and their target genes have been functionally characterized with respect to a role in synaptic function and learning. Additionally, sophisticated control mechanisms are emerging which can modulate miRNA function at the synapse in an activity dependent manner. It can be readily foreseen that detailed investigations into both synaptic miRNA-target interactions and the
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
Work in the laboratory of G. Schratt is funded by grants from the DFG (SFB488/SFB593/SFB636), the EU FP7 (ERC Starting Grant ‘Neuromir’), the EMBO Young Investigator Program, the Chica- and Heinz Schaller and the Siebeneicher Stiftung.
References (43)
- et al.
A novel pathway regulates memory and plasticity via SIRT1 and miR-134
Nature
(2010) - et al.
An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP
Proc Natl Acad Sci USA
(2008) - et al.
Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels
EMBO J
(2009) - et al.
Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microRNAs
Cell
(2010) - et al.
A coordinated local translational control point at the synapse involving relief from silencing and MOV10 degradation
Neuron
(2009) - et al.
FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A
J Neurosci
(2007) - et al.
Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex
Proc Natl Acad Sci USA
(2011) - et al.
Cells lacking the fragile X mental retardation protein (FMRP) have normal RISC activity but exhibit altered stress granule assembly
Mol Biol Cell
(2009) - et al.
Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA
Nat Neurosci
(2007) - et al.
Gene silencing by microRNAs: contributions of translational repression and mRNA decay
Nat Rev Genet
(2011)
MicroRNAs regulate brain morphogenesis in zebrafish
Science (New York, NY)
A microRNA feedback circuit in midbrain dopamine neurons
Science (New York, NY)
Cerebellar neurodegeneration in the absence of microRNAs
J Exp Med
Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration
Proc Natl Acad Sci USA
miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex
Development (Cambridge, England)
Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus
J Neurosci: Offic J Soc Neurosci
RNAase-III enzyme Dicer maintains signaling pathways for differentiation and survival in mouse cortical neural stem cells
J Cell Sci
MicroRNA loss enhances learning and memory in mice
J Neurosci: Offic J Soc Neurosci
Making synaptic plasticity and memory last: mechanisms of translational regulation
Genes Devel
Somatodendritic microRNAs identified by laser capture and multiplex RT-PCR
RNA (New York, NY)
Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain
J Neurochem
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Present address: Biochemisch-Pharmakologisches Centrum (BPC) Marburg, Institut für Physiologische Chemie, Philipps-Universiät-Marburg, Marburg, Germany.