MicroRNAs in neuronal function and dysfunction

doi:10.1016/j.tins.2012.01.004

Trends in Neurosciences

Volume 35, Issue 5, May 2012, Pages 325-334

https://doi.org/10.1016/j.tins.2012.01.004 Get rights and content

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.

Introduction

Profiling genome-wide mammalian transcriptional output (known as the transcriptome) has provided important insights into the complexity of RNA biology. Notably, mammalian cells expend large amounts of energy producing vast quantities of small and large RNA transcripts that do not code for protein, termed noncoding RNAs (ncRNAs). Short (∼22 nucleotides [nt]) ncRNAs, known as microRNAs (miRNAs), have been implicated in almost all aspects of cell biology. Here, we provide an overview of the role for miRNAs in brain development and function, and highlight recent findings implicating miRNAs in neurodevelopmental and neuropsychiatric disorders. We also discuss progress towards miRNA-based therapeutics to treat these conditions.

Section snippets

MicroRNAs in brain development and function

The enzymatic machinery and sequence of intracellular events involved in the biogenesis and maturation of miRNAs are highly conserved across animals and plants (Figure 1). In animals, miRNAs generally bind to the 3′ untranslated (3′UTR) region of target mRNA transcripts by incomplete complementation, particularly at the 5′ end of the miRNA, referred to as the seed region. Such pairing, which typically occurs via imperfect complementation in mammals, results in translational repression or

MicroRNAs and neuroplasticity

Dicer deletion in Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)-positive neurons in mice results in enhanced learning and memory [31], suggesting that miRNAs can maintain plasticity-related genes in translational repression until alleviated by neuronal activity. In fully differentiated neurons, miRNAs and much of the miRNA processing machinery is localized at dendritic spines and postsynaptic densities. This includes specialized cell granules known as processing bodies (P-bodies) that

Fragile X syndrome

Fragile X syndrome (FXS) is an X chromosome-linked disorder that is the most common cause of inherited intellectual disability (mental retardation), and is also a cause of autism. FXS results from loss of function of fragile X mental retardation protein (FMRP), encoded by the FMR1 gene. This loss of function results from an expanded number of CGG triplet repeats in the 5′UTR of FMR1, which when expanded greater than 200 triplets results in hypermethylation of the FMR1 promoter and consequently

Depression

Depression is a chronic and potentially life-threatening disorder characterized by low mood and loss of interest in otherwise pleasurable activities (anhedonia). Depression is thought to be related, at least in part, to deficits in serotonin transmission [65], because many therapeutic agents that are clinically efficacious for depression elevate serotonin transmission in brain. Emerging evidence suggests that miRNAs may be involved in the manifestation of depression and the therapeutic actions

MicroRNAs as targets for the development of therapeutics

Abnormally increased or decreased expression of various miRNAs may contribute to the pathophysiology of many neurodevelopmental and psychiatric disorders (above). Hence, replacement or inhibition of downregulated or overactive miRNAs, respectively, may be clinically beneficial in the treatment these disorders (e.g. 87, 88, 89, 90). Much effort has been directed toward developing modified oligonucleotide mimetics to replace, or antisense oligonucleotides (AOs) to inhibit, targeted miRNAs. A

Concluding remarks

The findings reviewed here demonstrate that miRNAs play key roles in all aspects of neuronal development, function and plasticity. Moreover, dysfunction in miRNA signaling contributes to neurodevelopmental and psychiatric disorders. Nevertheless, much work remains to be done to understand the precise mechanisms through which miRNAs regulate temporal and spatial dynamics of neuronal function, and to translate this knowledge into novel therapeutics for the treatment of neurological disorders.

Acknowledgments

Supported by a grant from the National Institute on Drug Abuse (NIDA) to P.J.K. (DA025983). We thank the Department of Biomedical Graphics at The Scripps Research Institute for assistance with graphics. This is publication number 20973 from The Scripps Research Institute.

References (128)

C. Liu
Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation
Cell Stem Cell
(2010)
N.K. Vo
MicroRNA pathways in neural development and plasticity
Curr. Opin. Neurobiol.
(2010)
H. Chen
miR-7 and miR-214 are specifically expressed during neuroblastoma differentiation, cortical development and embryonic stem cells differentiation, and control neurite outgrowth in vitro
Biochem. Biophys. Res. Commun.
(2010)
M. Coolen et al.
MicroRNAs in brain development and physiology
Curr. Opin. Neurobiol.
(2009)
E. Battaglioli
REST repression of neuronal genes requires components of the hSWI.SNF complex
J. Biol. Chem.
(2002)
E.V. Makeyev
The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing
Mol. Cell
(2007)
S.I. Ashraf
Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila
Cell
(2006)
S. Banerjee
A coordinated local translational control point at the synapse involving relief from silencing and MOV10 degradation
Neuron
(2009)
J. Krol
Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microRNAs
Cell
(2010)
D. Edbauer
Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132
Neuron
(2010)

S. Impey

An activity-induced microRNA controls dendritic spine formation by regulating Rac1-PAK signaling

Mol. Cell. Neurosci.

(2010)

H.Y. Cheng

microRNA modulation of circadian-clock period and entrainment

Neuron

(2007)

L.A. O’Neill

Boosting the brain's ability to block inflammation via microRNA-132

Immunity

(2009)

P. Rajasethupathy

Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB

Neuron

(2009)

R.S. Muddashetty

Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling

Mol. Cell

(2011)

Y. Xu

A polymorphism in the microRNA-30e precursor associated with major depressive disorder risk and P300 waveform

J. Affect. Disord.

(2010)

D.M. Santarelli

Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia

Biol. Psychiatry

(2011)

Y. Xu

MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia

Schizophr. Res.

(2010)

A.R. Mohn

Mice with reduced NMDA receptor expression display behaviors related to schizophrenia

Cell

(1999)

A.Z. Pietrzykowski

Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol

Neuron

(2008)

I.B. Levitan

miXED messages in ion channel modulation

Neuron

(2008)

F. Takeshita

Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes

Mol. Ther.

(2010)

J. Kota

Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model

Cell

(2009)

Y. Li

Emergence of chemical biology approaches to the RNAi/miRNA pathway

Chem. Biol.

(2010)

K. Watashi

Identification of small molecules that suppress microRNA function and reverse tumorigenesis

J. Biol. Chem.

(2010)

M. Kapsimali

MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system

Genome Biol.

(2007)

L.C. Cheng

miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche

Nat. Neurosci.

(2009)

A.J. Giraldez

MicroRNAs regulate brain morphogenesis in zebrafish

Science

(2005)

T.H. Davis

Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus

J. Neurosci.

(2008)

A. Schaefer

Argonaute 2 in dopamine 2 receptor-expressing neurons regulates cocaine addiction

J. Exp. Med.

(2010)

Y. Kawase-Koga

Different timings of Dicer deletion affect neurogenesis and gliogenesis in the developing mouse central nervous system

Dev. Dyn.

(2009)

T. Huang

Wnt1-cre-mediated conditional loss of Dicer results in malformation of the midbrain and cerebellum and failure of neural crest and dopaminergic differentiation in mice

J. Mol. Cell Biol.

(2010)

J. Bilen

A new role for microRNA pathways: modulation of degeneration induced by pathogenic human disease proteins

Cell Cycle

(2006)

S.S. Hebert

Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration

Hum. Mol. Genet.

(2010)

S. Martino

MicroRNA implications across neurodevelopment and neuropathology

J. Biomed. Biotechnol.

(2009)

J. Zhang

Effects of miR-541 on neurite outgrowth during neuronal differentiation

Cell Biochem. Funct.

(2011)

K. Abdelmohsen

miR-375 inhibits differentiation of neurites by lowering HuD levels

Mol. Cell. Biol.

(2010)

R.D Smrt

MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1

Stem Cells

(2010)

A.J. Kole

miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis

Genes Dev.

(2011)

P. Gaughwin

Stage-specific modulation of cortical neuronal development by Mmu-miR-134

Cereb. Cortex

(2011)

E. Balzer

LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro

Development

(2010)

R. Sanuki

miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression

Nat. Neurosci.

(2011)

N. Mellios

miR-132, an experience-dependent microRNA, is essential for visual cortex plasticity

Nat. Neurosci.

(2011)

P. Tognini

Experience-dependent expression of miR-132 regulates ocular dominance plasticity

Nat. Neurosci.

(2011)

L. Smirnova

Regulation of miRNA expression during neural cell specification

Eur. J. Neurosci.

(2005)

C. Conaco

Reciprocal actions of REST and a microRNA promote neuronal identity

Proc. Natl. Acad. Sci. U.S.A.

(2006)

M.E. Andres

CoREST: a functional corepressor required for regulation of neural-specific gene expression

Proc. Natl. Acad. Sci. U.S.A.

(1999)

J. Visvanathan

The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development

Genes Dev.

(2007)

X. Cao

A functional study of miR-124 in the developing neural tube

Genes Dev.

(2007)

W. Konopka

MicroRNA loss enhances learning and memory in mice

J. Neurosci.

(2010)

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Trends in Neurosciences

ReviewMicroRNAs in neuronal function and dysfunction

Introduction

Section snippets

MicroRNAs in brain development and function

MicroRNAs and neuroplasticity

Fragile X syndrome

Depression

MicroRNAs as targets for the development of therapeutics

Concluding remarks

Acknowledgments

Cell Stem Cell

Curr. Opin. Neurobiol.

Biochem. Biophys. Res. Commun.

Curr. Opin. Neurobiol.

J. Biol. Chem.

Mol. Cell

Cell

Neuron

Cell

Neuron

Mol. Cell. Neurosci.

Neuron

Immunity

Neuron

Mol. Cell

J. Affect. Disord.

Biol. Psychiatry

Schizophr. Res.

Cell

Neuron

Neuron

Mol. Ther.

Cell

Chem. Biol.

J. Biol. Chem.

MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system

Genome Biol.

miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche

Nat. Neurosci.

MicroRNAs regulate brain morphogenesis in zebrafish

Science

Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus

J. Neurosci.

Argonaute 2 in dopamine 2 receptor-expressing neurons regulates cocaine addiction

J. Exp. Med.

Different timings of Dicer deletion affect neurogenesis and gliogenesis in the developing mouse central nervous system

Dev. Dyn.

Wnt1-cre-mediated conditional loss of Dicer results in malformation of the midbrain and cerebellum and failure of neural crest and dopaminergic differentiation in mice

J. Mol. Cell Biol.

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Cell Cycle

Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration

Hum. Mol. Genet.

MicroRNA implications across neurodevelopment and neuropathology

J. Biomed. Biotechnol.

Effects of miR-541 on neurite outgrowth during neuronal differentiation

Cell Biochem. Funct.

miR-375 inhibits differentiation of neurites by lowering HuD levels

Mol. Cell. Biol.

MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1

Stem Cells

miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis

Genes Dev.

Stage-specific modulation of cortical neuronal development by Mmu-miR-134

Cereb. Cortex

LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro

Development

miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression

Nat. Neurosci.

miR-132, an experience-dependent microRNA, is essential for visual cortex plasticity

Nat. Neurosci.

Experience-dependent expression of miR-132 regulates ocular dominance plasticity

Nat. Neurosci.

Regulation of miRNA expression during neural cell specification

Eur. J. Neurosci.

Reciprocal actions of REST and a microRNA promote neuronal identity

Proc. Natl. Acad. Sci. U.S.A.

CoREST: a functional corepressor required for regulation of neural-specific gene expression

Proc. Natl. Acad. Sci. U.S.A.

Review
MicroRNAs in neuronal function and dysfunction