Physiol Rev 87: 799 – 823, 2007;
doi:10.1152/physrev.00036.2006.
Noncoding RNAs and RNA Editing in Brain Development,
Functional Diversification, and Neurological Disease
MARK F. MEHLER AND JOHN S. MATTICK
I. Introduction
II. RNA Editing
A. Targets of A-I RNA editing in the nervous system
B. Enzymes involved in A-I RNA editing
C. Adenosine deaminases that act on transfer RNAs
D. RNA editing in brain evolution and disease
E. Cytidine deaminases that act on RNA and DNA
F. Recoding of the genome, transcriptome, and proteome in brain development, learning,
and cognition
III. Small Nucleolar RNA
IV. MicroRNA
A. MicroRNAs in neural development
B. MicroRNAs in adult brain and brain disease
C. Tip of an iceberg?
V. Other Short Regulatory RNA
VI. Longer Noncoding RNA
A. Antisense RNAs
B. Other large noncoding RNAs
C. Noncoding RNAs in genomic imprinting
VII. Transfer RNA, Ribosomal RNA and Diseases of the Nervous System
VIII. Cytoplasmic Noncoding RNA in Synaptic Specialization and Function
IX. RNA-mediated Mechanisms Underlying Specific Neurological Diseases
X. Conclusion
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Institute for Brain Disorders and Neural Regeneration, Departments of Neurology, Neuroscience and
Psychiatry and Behavioral Sciences, Einstein Cancer Center and Rose F. Kennedy Center for Research in
Mental Retardation and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York; and
ARC Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience,
University of Queensland, St. Lucia, Queensland, Australia
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Mehler MF, Mattick JS. Noncoding RNAs and RNA Editing in Brain Development, Functional Diversification, and
Neurological Disease. Physiol Rev 87: 799 – 823, 2007; doi:10.1152/physrev.00036.2006.—The progressive maturation
and functional plasticity of the nervous system in health and disease involve a dynamic interplay between the
transcriptome and the environment. There is a growing awareness that the previously unexplored molecular and
functional interface mediating these complex gene-environmental interactions, particularly in brain, may encompass
a sophisticated RNA regulatory network involving the twin processes of RNA editing and multifaceted actions of
numerous subclasses of non-protein-coding RNAs. The mature nervous system encompasses a wide range of cell
types and interconnections. Long-term changes in the strength of synaptic connections are thought to underlie
memory retrieval, formation, stabilization, and effector functions. The evolving nervous system involves numerous
developmental transitions, such as neurulation, neural tube patterning, neural stem cell expansion and maintenance,
lineage elaboration, differentiation, axonal path finding, and synaptogenesis. Although the molecular bases for these
processes are largely unknown, RNA-based epigenetic mechanisms appear to be essential for orchestrating these
precise and versatile biological phenomena and in defining the etiology of a spectrum of neurological diseases. The
concerted modulation of RNA editing and the selective expression of non-protein-coding RNAs during seminal as
well as continuous state transitions may comprise the plastic molecular code needed to couple the intrinsic
malleability of neural network connections to evolving environmental influences to establish diverse forms of shortand long-term memory, context-specific behavioral responses, and sophisticated cognitive capacities.
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0031-9333/07 $18.00 Copyright © 2007 the American Physiological Society
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I. INTRODUCTION
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The mammalian and in particular primate nervous
systems are characterized by an unprecedented degree of
cellular diversity, anatomical asymmetries (laterality) and
specialized regional microdomains, regional interconnections, structural and functional plasticity, and exquisite
environmental responsiveness. These dual attributes of
modularity and adaptation are mediated by sophisticated
forms of cellular specialization and polarity, unique intracellular transport mechanisms, long-term adult neuronal
survival and maintenance of cellular traits, elaborate
membrane electrical and chemical properties, rapid and
robust homeostatic responses to environmental perturbations, elaborate afferent and efferent connections between mature nerve cells (i.e., synapses), and dynamic
activity-dependent alterations in synaptic strength underlying sophisticated cognitive functions such as higher
order intelligence, language, working memory, symbolic
representations, social organization, and adaptive behavioral repertoires (3).
These adult nervous system functional properties are
progressively elaborated in response to evolving developmental blueprints that include distinct sets of critical
periods designed to ensure that the fidelity of neural
network connections, propagated informational cues,
synaptic plasticity, and environmental responsiveness is
preserved throughout life (206, 207). Neural induction
from embryonic ectoderm, establishment of laterality and
axis formation within the evolving neural plate, threedimensional patterning of the neural tube, elaboration of
regional stem cell generative zones, and the development
of interconnections between specialized regional neuronal and glial cell types proceed through dynamic temporally and spatially mediated interactions between inductive signals from nonneural embryonic and extraembryonic cells and tissues and by intersecting axes of soluble
gradient morphogens. Thereafter, regional neural stem
cell subpopulations undergo self-renewal, expansion, cellular migration, progressive lineage restriction, progenitor
cell cycle progression and exit, neuronal and glial subtype
specification, progressive stages of neural cell differentiation, and mature neural trait elaboration including dendritogenesis, axonal path finding, synaptogenesis, and
neural network integration through the complex interplay
of gene-environmental interactions within context-dependent developmental settings.
A complex array of neurodevelopmental syndromes
and an interrelated spectrum of neurodegenerative diseases, neuropsychiatric disorders, and brain cancers result from aberrations of individual molecular and cellular
processes embedded within these progressive developmental stages and nested maturational events. The etiology of these diverse nervous system disorders is poorly
understood but likely involves mechanisms selective to
the nervous system such as those involved in regional
neural stem cell diversification, neuronal and glial subtype specification, long-term neuronal viability, stress responses and homeostasis, cellular polarity and intracellular transport, axodendritic process outgrowth, synaptic
specialization, stabilization and plasticity, and adaptations to environmental cues and insults.
It is known that the extent of non-protein-coding
sequences in eukaryotic genomes rises as a function of
developmental complexity (201), although the numbers of
genes and the extent of sequences encoding proteins (the
analog components of the system) remains relatively
static (86, 280). Humans appear to have barely more
protein-coding genes (55, 100) than the nematode worm
Caenorhabditis elegans (56), which has just 1,000 cells.
While some of this anomaly can be explained by increased
levels of alternative splicing in more complex organisms,
which increases the range and diversity of protein isoforms, it is also becoming apparent that the expanded
intronic and intergenic non-protein-coding sequences
themselves harbor large amounts of regulatory information, much of which may be transacted by RNA (280).
Although ⬍1.5% of the mammalian genome encodes proteins, at least 5% is apparently conserved (299), and recent
large-scale cDNA and genome tiling array transcriptomic
analyses have shown that most of the genome is transcribed, in complex patterns of nested and overlapping
transcripts with interlaced intron-exon structure, often
from both strands (36, 46, 86, 136, 137, 203). A significant
proportion of these transcripts are processed to form
large and small regulatory RNAs (reviewed in Refs. 203,
204) that act through sequence-specific recognition of
other RNAs and DNA to promote diverse developmental
programs through modulation of RNA structure, splicing
and stability, transcription and translation, as well as
chromatin architecture (82, 199, 200, 202, 255) and other
mechanisms (304).
Several distinct classes of non-protein-coding RNAs
(usually referred to simply as noncoding RNAs or
ncRNAs) are overly represented in the central and peripheral nervous systems (35, 47, 67, 119, 146, 154, 245, 249,
250). It is also clear that epigenetic mechanisms including
RNA editing (18, 288, 300) and the modulation of chromatin architecture, which is almost certainly RNA-directed
(25, 204, 255), are central to neural development as well
as mature function (35, 53, 119), adaptive responses
(4, 176), and dysfunction (26, 266, 282). In addition, genes
with large introns are strongly associated with neural
functions and processes and are significantly overrepresented among highly expressed genes in nervous system
tissues (271, 272, 280, 290). These observations suggest
that nervous system development, adult function, plasticity, and vulnerability to neurological disease states are
inextricably linked to, and may be fundamentally based
NONCODING RNAS IN NEURAL DEVELOPMENT, FUNCTION, AND DISEASE
on, the actions and potential perturbations of complex
and nuanced RNA regulatory networks.
II. RNA EDITING
A. Targets of A-I RNA Editing in the
Nervous System
It has been known for some time that transcripts
encoding proteins involved in fast neurotransmission, including voltage-gated ion channels and neurotransmitter
receptors, are subject to A-I editing (18, 288). However,
recent studies show that protein-coding genes involved in
neural signal propagation represent only a small subset of
edited transcripts in brain, which also include those from
loci encoding proteins involved in patterning of the evolving neural tube, neural stem cell self-renewal and progressive lineage restriction, neurogenesis and gliogenesis,
neural subtype specification, neuroblast migration, dendritogenesis and spine morphogenesis, axonal myelination and thermoregulation, synaptogenesis, neural network integration, DNA surveillance, repair and cell cycle
checkpoint control, cellular stress and senescence pathways, pro- and antiapoptotic signaling cascades, ubiquitin-proteasomal and autophagy protein turnover pathways, endosomal trafficking/vesicular transport, nuclear
envelope and matrix organization and nucleocytoplasmic
shuttling, epigenetic and RNA regulatory circuitry, energy
metabolism and cellular homeostasis. They also include
transcripts from other loci involved in neurodevelopmental, neurodegenerative, neuropsychiatric disorders as well
as protooncogenes and tumor suppressor genes involved
in central nervous system (CNS) neoplasia (13, 27, 117,
175, 191, 215, 288). This extraordinary repertoire of targets suggests that RNA editing in the nervous system is
involved in all aspects of neural development, mature
steady-state functions, synaptic and neural network plasticity, as well as preservation of genomic as well as cellular integrity against a wide variety of intracellular and
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environmental stressors that predispose to neurodevelopmental, neurodegenerative and neuropsychiatric diseases, and nervous system neoplasia.
A-I RNA editing of targeted substrates in the nervous
system can alter the functional properties of proteins,
silence constitutive activity, and modulate RNA translation, localization, and stability (18). In addition to changing codons in mRNA (18), A-I editing also has the capacity
to modulate splice site choice (171), small nucleolar RNA
precursors (191), endogenous antisense RNAs (140) and
miRNA target diversity (28), miRNA processing (310), and
other ncRNA and ribonucleoprotein complex targets
(175), further attesting to the functional complexity of
RNA regulatory networks. Recent evidence implicates
ADARs and A-I editing in chromatin modification and
possibly in genomic imprinting and X-chromosome inactivation, indicating the interplay between these processes
and RNA-based silencing mechanisms (83, 288). Moreover, ADAR2-mediated editing of RNA substrates in the
nucleolus may be inhibited by snoRNAs (291); ADAR2
activity can be modulated by sequestration in the nucleolus and nucleolus-nucleoplasm shuffling (256), and
ADAR mRNA itself is subject to editing which restricts its
function in the adult, at least in Drosophila (142).
B. Enzymes Involved in A-I RNA Editing
There are three A-to-I RNA editing enzymes (ADAR1–3)
in mammals, all differentially expressed during organogenesis with ADAR3 restricted to brain and ADAR1 and
ADAR2 preferentially expressed in the nervous system
(18, 45). RNA editing also displays complex and dynamic
profiles of subcellular localization and spatiotemporal expression during progressive stages of nervous system
maturation (24, 157, 169, 234). Furthermore, RNA editing
is modified by behavioral state and modulated by genetic
background (79). Moreover, the activity profiles and molecular properties of ADARs can be orchestrated by
changing environmental signals including inflammation
and by feedback regulation (18, 288, 309). All ADARs
normally exist as functional homodimers, although
ADAR3 requires additional CNS environmental cues to
undergo dimerization and ADAR1 isoforms can also exist
as “internal” heterodimers (49). Multiple isoforms of
ADAR1 and ADAR2 are observed, and ADAR1 displays
preferential tissue-specific promoter utilization whereas
ADAR2 exhibits more pronounced alternate splicing of
multiple exons to each generate a broad array of protein species with unique enzymatic properties and remarkable degrees of molecular diversity (94, 139). Different ADARs can also edit multiple different sites
on the same RNA species with diverse functional
outcomes (288).
The potential biological roles of ADAR3 in the nervous system are particularly intriguing because of its
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RNA editing is a dynamic and versatile posttranscriptional mechanism of base recoding catalyzed by specific
classes of editing enzymes that can significantly modify
the functional properties and levels of expression of a
spectrum of protein-coding mRNAs as well as influence a
potentially broad array of ncRNAs (18, 140, 222, 288).
Although various forms of RNA editing are known to
occur throughout the metazoa, a dramatic increase of
RNA editing has occurred during mammalian evolution,
with the hominid lineage exhibiting the highest levels and
the most complex forms of editing of individual transcripts. Moreover, adenosine to inosine (A-I) RNA editing
catalyzed by adenosine deaminases acting on RNAs
(ADARs) is particularly active in the brain (18, 288).
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MARK F. MEHLER AND JOHN S. MATTICK
C. Adenosine Deaminases That Act
on Transfer RNAs
An additional level of regulatory control involving
RNA editing is suggested by the ability of ADARs to act in
concert with ADATs that modify tRNAs to change codon
recognition during mRNA decoding (288). All eukaryotes
possess ADAT1–3, and ADAT heterodimers are common
(49, 144). ADATs are present in the embryonic and adult
nervous system and are thought to influence the stability
and structural properties of tRNAs to enhance the fidelity
and efficiency of tRNAs in decoding mRNAs and in generating protein diversity (95, 143, 258). Interestingly, a
mutation in the “editing” domain of a specific aminoacyltRNA synthetase results in mischarged tRNAs, intracellular accumulation of misfolded proteins in neurons, and
induction of the endoplasmic reticulum-mediated unfolded protein stress response with associated neurodegeneration (172). Mischarged tRNAs are normally cleaved
by the editing function of aminoacyl-tRNA synthetases
through the actions of a domain distinct from the aminoacylation domain (172). Genomic clustering, structural similarities, and environmental responsiveness
between aminoacyl-tRNA synthetases and ADATs suggest that these enzymes may play complementary roles
in enhancing the fidelity of protein translation and in
promoting structural and functional diversification
(185, 190, 259).
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D. RNA Editing in Brain Evolution and Disease
These general observations suggest that RNA editing
may promote molecular and informational diversity by
modulating both RNA and protein regulatory networks.
Analysis of ADAR mutants in C. elegans, Drosophila, and
mice demonstrate that the process of RNA editing is
essential for nervous system cognitive and behavioral
functions and has been further coopted for essential roles
in the mammalian brain (246, 286, 296). Finally, deregulation of RNA editing resulting in uncorrected forms of
hyper- or hypoediting has been implicated in a spectrum
of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders (reviewed in Ref. 288).
In humans, A-I editing occurs far more frequently
than has been previously appreciated, with the vast majority of the editing occurring in a subclass of primatespecific short interspersed nuclear elements (SINEs) consisting of inverted Alu repeats predicted to form intramolecular duplexes in noncoding RNA sequences in introns,
intergenic transcripts, untranslated regions (UTRs) and
nontranslated exons, but not in translated exons or in the
mitochondrial genome (13, 27, 175). The predominance of
human A-I RNA editing over similar forms of editing in
lower organisms has recently been shown to be due to
unique properties of the single SINE (Alu) element active
in the primate lineages as opposed to those SINE elements present in lower mammals (B1, B2, ID, B4): long
repeat length, prevalence and lack of evolutionary divergence (223), the latter of which is most easily explained
by functional selection mitigating against mutational drift.
In addition, through a wide spectrum of molecular mechanisms, Alu elements appear to exert their effects at all
levels of gene regulation with profound effects on speciation, gene-environmental interactions, ontogeny,
homeostasis, and stress modulation and susceptibility to
disease (105) and may therefore represent an important
driving force in primate evolution. Indeed, these observations strongly suggest that the predominance of Alu elements in the human genome may not represent an idiosyncratic but otherwise evolutionary neutral invasion of
the primate lineage by this class of SINEs, but rather be
the result of positive selection for these sequences as a
modular substrate for A-I editing, in turn driven by positive selection for increased brain capacity and cognitive
complexity in the primate lineage.
E. Cytidine Deaminases That Act on RNA and DNA
An additional class of editing enzymes is represented
by the cytidine deaminases that can act on both RNA and
DNA by changing cytidine (C) and deoxyC (dC) to uridine
(U) and deoxyU (dU), respectively (222). The apolipoprotein B editing catalytic subunit (APOBEC) editing family
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broad substrate specificity (binding single-stranded as
well as double-stranded RNA), its selective presence in
restricted brain regions and postmitotic neurons, and its
ability to act as a dominant negative for both ADAR1 and
ADAR2 (45), strongly implying that it can form heterodimers with ADAR1 and ADAR2, further adding to the
functional complexity of these enzymes in the brain. Environmentally responsive forms of ADARs (the interferoninducible p150 long cytoplasmic isoform of ADAR1 that
selectively targets endogenous antisense RNA pathways)
and those species with unique ADAR modulatory roles
and substrate specificity (ADAR3) exhibit selective regional developmental and mature nervous system expression. Moreover, the crystal structure of the catalytic domain of human ADAR2 reveals that inositol hexakisphosphate (IP6) is buried within the enzyme core, implying a
link to cell signaling (192). Moreover, amino acids that
coordinate IP6 in ADAR2 are also conserved in adenosine
deaminases that act on transfer RNAs (ADATS; see below), and there is evidence that IP6 is required for ADAT
activity (192). These observations highlight the potentially
central roles of RNA editing in brain evolution (see below), gene-environmental interactions during nervous
system ontogeny, and functional specialization during
neural maturation.
NONCODING RNAS IN NEURAL DEVELOPMENT, FUNCTION, AND DISEASE
Physiol Rev • VOL
actions of AID result in hematolymphopoietic malignancies, solid tumors, and chromosomal translocations (236).
To effectively carry out its myriad of enzymatic roles
required to generate unusual degrees of molecular and
informational diversity, a spectrum of DNA repair enzymes is coopted to assist AID in repairing DNA nicks and
double-strand breaks necessary to maintain genomic integrity during active transcription and also in generating
additional surrounding mutations to further enhance AIDmediated molecular diversity and plasticity (37, 73, 186,
236). The use of different classes of DNA repair enzymes
(base excision repair, mismatch repair, nonhomologous
end-joining, and translesional synthesis error-prone Y-family
DNA polymerases) for diverse AID-dependent biological
processes, substrates and stages of enzymatic process
elaboration ensure that transcription-coupled repair is
efficiently carried out and is coupled to ongoing mutational activities of specific DNA sequences for the generation of additional dynamic forms of informational processing (37, 73, 170, 186, 236). Recent studies suggest
that postmitotic neurons present unique challenges to
genomic integrity because of the presence of high transcriptional activity in the absence of active DNA replication, unusual degrees of oxidative stress, and selective
reductions in key classes of DNA repair enzyme pathways
with the exception of transcription-coupled repair (205,
233). Additional reports suggest that dynamic changes to
the genome, the transcriptome, and the machinery of
protein translation and function may play previously unimagined roles in neuronal network functions, information processing, and environmental communications (16,
52, 149, 247, 269, 270).
F. Recoding of the Genome, Transcriptome, and
Proteome in Brain Development, Learning,
and Cognition
These overall observations suggest the novel hypothesis that the global sphere of “RNA editing” may provide
the molecular foundations for brain development and
function, i.e., for the transfer, encoding, consolidation,
retrieval, and long-term integration of sophisticated environmental inputs into both infinitely malleable as well as
stable informational traces through neural network activities mediated by dynamic and interactive RNA, DNA, and
protein regulatory circuits operating in real-time spatiotemporal synchrony. Indeed, the fact that mRNAs, tRNAs,
and rRNAs (rather than synthesized proteins) are trafficked to synaptic termini (148, 153, 285) may be mandated by the requirement for RNA editing to occur specifically in these places to modulate synaptic activity and
synaptic connectivity in response to local environmental inputs, and that these changes are communicated
back to the nucleus by the retrograde trafficking of the
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consists of several members including APOBEC1, -2
CEM15, and activation-induced cytidine deaminase (AID)
in mice and APOBEC1, 2, 3A-H, and AID in humans. Each
APOBEC-related protein (ARP) possesses intrinsic substrate specificity through recognition of unique cis-acting
sequences/structures or through the actions of trans-acting factors that confer site preferences (300). C-to-U editing of apolipoprotein mRNA by APOBEC1 is thought to
reduce the incidence of nonsense mediated RNA decay
(300). Overexpression of APOBEC1 results in hyperplastic and neoplastic diseases due to loss of editing fidelity
and stabilization of cytoplasmic mRNAs encoding
growth-promoting proteins (300). Similarly, inactivation of APOBEC1 or overexpression of APOBEC1 resulting in formation of a stop codon in neural tumors from
patients with neurofibromatosis type 1 prevents the
GTPase activating protein neurofibromin from properly modulating the Ras signaling pathway (216, 273,
300). There are eight human APOBEC3 enzymes
(APOBEC3A-H) that probably arose from a primordial
cytidine deaminase through a series of tandem gene duplications followed by rapid divergent evolution (300).
The mouse CEM15 gene exhibits structural homology to
APOBEC3G and resides on chromosome 15, which is
syntenic to human chromosome 22, the location of the
APOBEC3 gene family (300). APOBEC3 is overexpressed
in various cancers, suggesting that it functions as a protooncogene (222). APOBEC3 family members exhibit distinct editase activities, significant alternate splicing, presence or absence of pseudogenes, and DNA mutator functions (300). APOBEC3 isoforms play essential roles in
restriction of transposition of endogenous retroelements
and in antiretroviral events (210, 300). APOBEC3G is
selectively present in primate pyramidal neurons but not
glial cells within the cerebral and cerebellar cortices in a
nuclear pattern that is distinct from its cytoplasmic subcellular localization in peripheral tissues (113). Interestingly, APOBEC3G displays special roles in cell growth
and cell cycle regulation and functions as a cytidine
deaminase for both RNA as well as DNA (300).
APOBEC3G protects against retroviral infection by
deaminating first-strand cDNA synthesis catalyzed by reverse transcriptase, thus establishing links between recoding of RNA and DNA (113, 300).
Perhaps the most interesting ARP is AID, a cytidine
deaminase acting preferentially on DNA but also on RNA,
which is present almost exclusively in maturing B cells in
the germinal centers of secondary lymphoid organs and at
lower levels in human brain (220, 300). AID acts on singlestranded DNA of actively transcribed genes rather than
double-stranded DNA or DNA/RNA hybrids by converting
dC to dU (78, 170, 186). During later stages of B-cell
affinity maturation, AID promotes class switch recombination and somatic hypermutation as well as gene conversion in certain contexts (78, 218, 300). Inappropriate
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MARK F. MEHLER AND JOHN S. MATTICK
III. SMALL NUCLEOLAR RNA
Another important and previously underappreciated
form of posttranscriptional RNA processing is mediated
by a class of noncoding RNAs termed small nucleolar
RNAs (snoRNAs). These RNAs range from 60 to 300 nucleotides in length and orchestrate the site-specific modification of nucleotides in target RNAs through the twin
processes of 2⬘-O-ribose methylation and pseudouridylation, modulated by the box C/D and box H/ACA snoRNAs,
respectively (15, 174, 208). Most of the known snoRNAs
are involved in rRNA modifications during ribosomal biogenesis and are localized in the nucleolus. A subset of
related RNAs (scaRNAs) guide modifications of spliceosomal RNAs and reside within cytoplasmic Cajal bodies
(208). Members of the greater snoRNA superfamily have
been implicated in a broad array of biological processes
including alternate splicing, transcription, chromosome
maintenance and segregation, genomic imprinting, and
cell cycle regulation (121, 250, 253) and have also been
shown to be subject to imprinting (263). Thus it appears
likely that RNA modifications are utilized as a global
Physiol Rev • VOL
mechanism of gene regulation and that many additional
snoRNA species and subtypes remain to be identified and
interrogated.
Multiple brain-specific snoRNAs have been identified
in mice (MBI-36, MBII-13, MBII-48, MBII-49, MBII-52,
MBII-78, and MBII-85), all representatives of the C/D
class with the exception of MBII-13, a constituent of the
H/ACA class (39, 122, 250). Human homologs of these
snoRNAs also display high levels of expression in the
nervous system (39). Interestingly, individual snoRNAs
(RBI-36) exhibit genus-specific (rat) brain functions.
These overall observations further suggest that snoRNAs
exhibit a broad range of nonhousekeeping regulatory
functions in brain (40).
In situ hybridization analysis in adult mouse brain
has shown that several snoRNAs (MBI-36, MBII-48,
MBII-52, MBII-85) have greatest expression in the hippocampus and amygdala, areas associated with learning
and memory (251). Within these specialized brain regions
there is an additional preferential stratification of expression between the hippocampal CA1 region (MBII-48) and
the dentate gyrus (MBII-85). Moreover, MBI-36, MBII-48,
and MBII-52 display greater ventral than dorsal hippocampal expression profiles.
The ventral hippocampus is known to be involved in
contextual conditioning, and therefore, it is interesting to
note that the expression of MBII-48 and MBII-52 but not
MBI-36 and MBII-85 are transiently modulated during
contextual memory consolidation (fear conditioning)
(251). In addition, during the time scale associated with
immediate early gene modulation (1.5 vs. 25 h), MBII-48
displays transient downregulation, whereas MBII-52 displays upregulation. These observations suggest that the
stimulus association regulates specific snoRNA expression during the process of storage of learned memories.
HBII-52 modifies the expression of the serotonin
5-HT (2C) receptor subunit, involved in memory consolidation, including alternate splicing and A-I RNA editing
(151). In Prader-Willi syndrome, HBII-52 is not expressed
and serotonin 5-HT (2C) receptor isoforms distinct from
those that characterize normal expression patterns are
elaborated (151). This suggests that anomalous splicing
may contribute to the pathogenesis of this developmental
syndrome associated with genomic imprinting. HBII-13,
HBII-52, and HBII-85 map to the Prader-Willi syndrome
locus, thereby suggesting that snoRNAs may actively participate in genomic imprinting (250). A significant array of
other classes of noncoding RNAs are also intimately associated with the process of genomic imprinting, a still
poorly understood mechanism of allele-specific gene silencing that clearly affects brain development and function in a variety of ways (see below). It is interesting to
note that the small nucleolar ribonucleoprotein particles
that contain H/ACA box snoRNA also contain the protein
NAP57/dyskerin that is highly expressed in embryonic
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RNAs either as ribonucleoprotein complexes or as
granules (19).
This also suggests the even more radical hypothesis
that memory and cognition obtained through the interaction of the environment and the nervous system is in fact
secured and subsequently hard-wired by direct genomic
modification in individual cells, given that cytidine deamination is involved in mutation and splice variant switching in B cells (78, 218, 300), which also would explain the
particular sensitivity of the immunological and nervous
systems to mutations in DNA surveillance, repair, and
editing enzymes (91, 96). Whether the nervous system
experiments directly with such changes followed by functional clonal selection, as occurs in generating antibody
diversity in the immune system, or has such changes
rewritten back to the DNA following a productive functional outcome of RNA editing, i.e., RNA-directed DNA
modification, is a moot point, but the latter hypothesis has
the attraction that the genomes of cells in the brain can
evolve in situ, with or without clonal expansion, in response to experience. If correct, this hypothesis predicts
not only that alterations to this system will result in neural
defects, but also that individual neural cells will in fact
have distinctive spatially and temporally defined genome
sequences, different from the parental genotype, which
can be tested by sequencing. Indeed, this may be the
source of many variant transcripts currently thought to be
the immediate (as opposed to historical) result of RNA
editing. It also predicts that memory consolidation should
be inhibited by short-term knockdown of the relevant
enzymes (e.g., by RNA interference).
NONCODING RNAS IN NEURAL DEVELOPMENT, FUNCTION, AND DISEASE
neural tissues including cerebellar Purkinje cells and mitral cells of the adult olfactory bulb (112).
IV. MICRORNA
A. MicroRNAs in Neural Development
Zebrafish dicer mutants that are defective in miRNA
processing exhibit defects in neural induction, neural
plate and neural tube formation and three-dimensional
patterning, segmental morphogenesis, neural stem cell
self-renewal, proliferation, progressive lineage restriction,
and axonal path finding (97, 98). These defects are largely,
although not completely, rescued by complementation
with the miRNA miR-430 (97, 98). These findings suggest
that individual miRNAs can induce large-scale spatiotemporally mediated changes in the transcriptome. miR-430
shares origins with miR-302 and miR-372, which are
both present in embryonic stem (ES) cells (118). Multiple
miRNAs also exhibit both overlapping and inverse expression patterns to those of Hox segmentation genes, thus
suggesting additional levels of complexity in the mechanisms of neural gene regulation (195, 232).
The presence of minor neuronal defects in later developmental stages in miR-430 rescue experiments of
dicer mutants demonstrates that other miRNAs and/or
short interfering RNAs (siRNAs) are involved in later
stages of neural development and maintenance of mature
neural cell fates (97, 98). A large group of miRNAs is
involved in human ES cell maintenance (279), a subset of
which affect subsequent neural development. During ES
cell-derived neurogenesis in vitro and in vivo, miR-124a
and miR-9 differentially enhance neural lineage elaboration by positively promoting neurogenesis while actively
inhibiting gliogenesis, respectively, through STAT3-mediated developmental signaling pathways (167). Overexpression or inhibition of brain-specific miRNAs disrupts
the balance between neurogenesis and gliogenesis and
the normal temporal transition from neurogenesis to glioPhysiol Rev • VOL
genesis (35, 47, 154, 164), thereby demonstrating the intricate combinatorial profiles of miRNA-mediated sensor
and effector state transitions.
In mice, there are numerous brain-specific miRNAs,
with miR-124 being the most abundant (47, 166, 180, 306).
Approximately 20% of these miRNAs exhibit regulated
expression during neural development with a subset upregulated during retinoic acid-induced neural cell differentiation from embryonic carcinoma cells (141, 275).
Conversely, experimental downregulation of miR-23
significantly enhanced the Notch pathway-associated
transcriptional repression mediated by the downstream
effector Hes1, with concurrent preservation of the selfrenewing neural stem cell basal state (141). Several predicted targets of miRNAs, such as Notch, PTEN, and IDs
(inhibitors of differentiation), are important mediators of
neural stem cell self-renewal and exhibit coordinate regulation (47, 104, 252). Components of the pri-miRNA processing complex including DGCR8 and Drosha are
present in embryonic neural stem cell generative zones
(102, 268), and deletion of DGCR8 results in DiGeorge
syndrome, a multisystem disorder associated with significant learning disabilities. During progressive stem cell
lineage restriction, dynamic switches in expression profiles of miRNA families occur (141, 164, 167, 275).
The Drosophila ortholog of miR-124 is also entirely
restricted to the developing central nervous system, suggesting that this miRNA and others that exhibit expression patterns analogous to those of their vertebrate counterparts have ancient roles in developmental patterning
(2). Many other miRNAs are specifically transcribed in
subsets of cells in the embryonic brain and the ventral
nerve cord in Drosophila, including miR-315, miR-92a,
and miR-7 (2), whose fish and mammalian orthologs are
also upregulated in brain (213, 302). Other miRNAs display expression in the embryonic peripheral nervous system in Drosophila (2).
A wide variety of miRNAs are localized to mammalian neuronal subtypes, with the highest concentration
observed in the cerebral cortex and the cerebellum (164,
167). Additional miRNAs are present predominantly
within glial cell subtypes, with other miRNAs exhibiting
more global or neural stem/progenitor cell-specific patterns of expression (154, 166, 275). These observations
generally suggest that there is extensive cross-talk between transcriptional and posttranscriptional regulatory
mechanisms and distinct miRNAs that are active within
particular neural cell lineages. During progressive stages
of cortical development, a distinct subset of miRNAs
displays increased levels of expression while others do
not (166).
Neural transcription factors also appear to be miRNA
targets (114, 154). Conversely, specific proneural basic
helix-loop-helix transcription factors upregulate miRNA
expression, including expression of miR-124 which has
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MicroRNAs (miRNAs) are short (⬃22 nucleotide)
regulatory molecules that modulate the translation or
stability of target RNAs (reviewed in Refs. 204, 316).
Despite their relatively recent discovery, it is already clear
that miRNAs play important roles in nervous system development including neurulation, neural tube patterning,
segmental morphogenesis, laterality, neural stem cell selfrenewal, proliferation, lineage restriction, neuronal and
glial lineage specification, differentiation, polarity, dendritogenesis, axonal path finding, apoptosis, protein turnover, cell positioning, and maintenance of mature neural
traits. They also play key roles in a range of neurodevelopmental, neurodegenerative, and neuropsychiatric diseases as well as in brain cancer.
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B. MicroRNAs in Adult Brain and Brain Disease
miRNAs are also expressed at high levels within the
mature and even the senescent brain and function to
orchestrate the maintenance of adult neural cell traits, to
promote cellular homeostasis and dampen endogenous
and exogenous stress responses, and to modulate multiple parameters associated with synaptic plasticity (47, 54,
127, 261, 265, 275). By repressing the expression of genes
involved in maintaining the undifferentiated neural cell
state, miRNAs promote the fidelity of specific differentiated neural phenotypes (164, 166). Therefore, nonsancPhysiol Rev • VOL
tioned alterations in the profiles of expression of miRNAs
may induce dedifferentiation and cellular transformation.
In the highly malignant glial cell-associated brain tumor,
glioblastoma multiforme, there is dramatic overexpression of miR-21, whereas in other neural tumors, including
more benign grades of gliomas, there are significantly
lesser degrees of miR-21 overexpression (43). Additional
experimental studies indicate that aberrant expression of
miR-21 specifically blocks gene products essential for
glial cell differentiation or apoptosis, thereby favoring
tumorigenesis (43).
The largest subgroup of predicted miRNA targets
include transcripts encoding synapse-associated proteins
such as synapsin 1, synaptotagmin, and the fragile-X mental retardation protein (FMRP) (129). Numerous studies
suggest that miRNAs are intimately involved in synaptic
tagging to ensure synaptic input specificity during the
critical phases of memory formation (146, 197, 257).
miRNAs are present in dendritic spines and reversibly
interact with the cellular machinery to produce longlasting changes in synaptic function (146, 261). In response to synaptic activity, changes in the RNA-induced
silencing complex (RISC) or conformational alterations in
dendritic mRNAs involving accessibility to their 3⬘-UTRs
promote siRNA- and miRNA-mediated silencing (12, 188).
miRNAs can participate exclusively in both processes by
the actions of Loquacious, the miRNA equivalent of the
executor step of RNA interference (RNAi) (242, 311).
Interestingly, Arabidopsis miRNAs 173 and 390 are
known to target the primary transcripts encoding transacting siRNAs (6). These sites of RNA complementarity
set the register for the mature siRNA molecules and promote siRNA phasing, thus illustrating the dual functions
for miRNA in RISC-mediated silencing (6).
In addition, certain miRNA precursors undergo RNA
editing by ADAR1/2 with suppression of processing by
Drosha and degradation by Tudor-SN (187, 310). It has
also been reported that RNA editing increases the diversity of miRNAs and their targets, thereby modulating
miRNA function (28). Some miRNA genes are also subject
to imprinting (262). In addition, polymorphisms in the
pre-miRNA hairpin region may alter target selection with
significant biological consequences (e.g., C3 A in mature
miR-30c-2) or may disrupt stem integrity and thereby
influence miRNA processing (124). Additional variations in their promoter regions have significant implications for miRNA expression levels. These different
types of miRNA-associated polymorphisms affect the
expression of seminal neurodevelopmental proteins
and may be a mechanism for the advent of neurological
diseases.
Putative targets for miRNAs include mRNAs encoding proteins involved in all aspects of neural development,
maintenance of neuronal function, and neural network
plasticity throughout the neuraxis and concurrently in
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the ability to bind to the most abundant miRNA response
element in the 3⬘-UTR and to downregulate the expression of at least 100 mRNAs (154, 180, 297).
In a mouse knockout (KO) model of presenilin 1, the
gene mutated in a subset of early familial forms of Alzheimer’s disease (AD), there are profound alterations in
embryonic cortical development and precocious neurogenesis (166). Microarray analysis in this presenilin 1
KO model has revealed selective dysregulation of two
miRNAs, miR-9 and miR-131. These brain-enriched
miRNAs are derived from the arms of the stem of a
common miRNA precursor and show independent developmental regulation but coordinate depletion during a
late-stage embryonic critical period. miR-9 also regulates
the expression of ID2, a negative regulator of neural stem
cell lineage maturation, and miR-131 modulates the expression of calcineurin A␤, a cofactor for calcium-mediated neuronal Sp1 transcription activation (166). Interestingly, Sp1 and other C2H2-type zinc-finger transcription
factors have been reported to have a high affinity for its
binding motif in RNA:DNA forms (267), suggesting that
RNA signaling may control transcriptional activity as
well, a possibility supported by a range of other evidence (57, 82, 178, 203).
Lateralization of the chemosensory organs of C. elegans
is mediated by the asymmetric expression of the miRNAs
miR-273 and lsy-6 with differential translational block of
die-1 and default (miR-273) or induced (lsy-6) elaboration of the right- or the left-sided representative of this
essential neural structure, respectively (44). The brainspecific miRNA miR-134 is localized to the synaptodendritic compartment of rat hippocampal neurons and negatively modulates the size of dendritic spines by inhibition
of translation of the protein kinase Limk1 mRNA (261).
Brain-derived neurotrophic factor (BDNF) is thought to
relieve the miR-134-mediated translational inhibition
with promotion of synaptic development, maturation, and
plasticity through modification of the activities of additional transcriptional regulators within the miR-134 complex rather than by dissociation of miR-134 from Limk1
mRNA (261).
NONCODING RNAS IN NEURAL DEVELOPMENT, FUNCTION, AND DISEASE
C. Tip of an Iceberg?
The known miRNAs are generally those that are
abundant, are highly conserved, and have multiple targets
(204), the latter of which accounts for their high evolutionary conservation (204). This in turn implies that there
will be many others, perhaps tens or hundreds of thousands of undiscovered miRNAs that are not so constrained and that can evolve quickly or be easily born to
explore new connections in regulatory networks, and that
act in particular cell types and even individual neurons.
The latter is exemplified by the example of lsy-6 in
C. elegans, which was only discovered by sensitive genetic screens, and which required extraordinary biochemical analyses to confirm its existence (131). Recent studies have identified many new human miRNAs, a significant number of which appear to be primate specific
(21–23). It is also clear that miRNA expression profiles are
progressively elaborated as the developmental program
unfolds and cellular differentiation proceeds, again suggesting that many if not most may be cell specific (277,
302). Deep sequencing of ⬃274,000 small RNAs in human
colorectal cancers and normal colonic mucosa showed
that the levels of different miRNAs can vary by up to four
orders of magnitude and that the discovery rate of novel
miRNAs was linear between 50,000 and 274,000 tags;
these and other similar studies suggest that there are
many more low-abundance miRNAs yet to be identified
(22, 23, 61). Finally, these conclusions are supported by
whole chromosome tiling array transcriptome analyses
which indicate that there is on average 1 short (⬍200 nt)
RNA expressed approximately every 3 kb (T. Gingeras,
Physiol Rev • VOL
personal communication), as well as the presence of large
numbers of plausible miRNA precursor structures in the
human genome, many of which appear to be expressed in
the brain (L. J. Croft and J. S. Mattick, unpublished observations) and may have specific roles in determining
function and cell identity in the nervous system.
It is also likely that there are many hundreds if not
thousands of as-yet-undiscovered cell- and tissue-specific
snoRNAs and sno-like RNAs, as well as new classes of
regulatory RNAs, such as the recently described piRNAs
that are specifically expressed in the testis (8, 99), the
other tissue apart from brain that shows an extraordinarily rich expression of noncoding RNAs (245). It is also
worth noting that many snoRNA and miRNA genes are
clustered and that most snoRNAs and many miRNAs are
encoded within introns of both protein-coding and noncoding genes (including imprinted genes) (204, 263), testimony to the complexity of the genetic output and the
parallel functional and regulatory networks in which
these gene products participate (199). The presence of
bifunctional or polycistronic RNAs may be much more
widespread than previously believed and not restricted to
transcripts capable of being processed to miRNAs or
snoRNAs. The specificity and complexity of small ncRNA
expression and putative mechanisms of action almost
certainly play a central role in brain development, mature
nervous system functioning, disease states, and neural
regenerative responses.
V. OTHER SHORT REGULATORY RNA
An important variation on the theme of short transacting RNAs is a double-stranded neuron-restrictive silencing element (dsNRSE) RNA that exhibits a striking
structural resemblance to a miRNA (168). However,
dsNRSE RNA does not act as a negative regulator of
translation but rather as a transcriptional activator of
neuronal differentiation genes by converting the neuronal
silencer factor (REST/NRSF) and its extensive and everchanging epigenetic regulatory complex components
from a transcriptional repressor in undifferentiated, nonneural, and nonneuronal cells to a transcriptional activator during early neuronal lineage elaboration (168). REST
has recently been shown to modulate the expression of a
subset of miRNAs including the brain-specific miR-124a
(54). In undifferentiated and nonneuronal cells, REST
inhibits miR-124a expression through the RE-1 promoter
gene silencer element, whereas during neuronal maturation alleviation of REST repression allows miR-124a to
selectively degrade nonneuronal transcripts, thus providing a regulatory link for REST-independent miRNAs acting in concert with the actions of dsNRSE RNA in complementary transcriptional and posttranscriptional neuronal contexts.
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specific disorders of the developing, mature, and aging
nervous system. Predicted miRNA targets include numerous proteins implicated in neurodevelopmental and neurodegenerative diseases (249). Tourette’s syndrome has
been shown to manifest clinically as a result of sequence
variations in the docking site for miR-189 in the SLIT and
Trk-like family member 1 (SLITRK1) mRNA (1). It has
previously been shown that SLITRK1 is required for progressive stages of neuronal maturation and its expression
profile is deregulated in several distinct neural tumor
subtypes (10, 11). In a type of early-onset Parkinson’s
disease (Waisman syndrome) and in a form of X-linked
mental retardation (MRX3), there are alterations associated with the gene locus of miR-175 (77). Additional
studies have implicated miRNAs in a spectrum of neuropsychiatric diseases associated with developmental
pathogenesis (249), and there is evidence that mutations
involved in creating or destroying putative miRNA target
sites are abundant in mammalian genes and might be
important causes of phenotypic variation (50), including
psychological variation.
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MARK F. MEHLER AND JOHN S. MATTICK
VI. LONGER NONCODING RNA
A. Antisense RNAs
Natural antisense RNAs (i.e., RNAs that are expressed from and may potentially interact directly with,
and/or regulate the expression of, protein-coding transcripts from the other strand of the same locus) are
greatly enriched in the nervous system (161). These antisense RNAs exhibit dynamic developmentally regulated
and spatially discrete expression profiles and are observed in over 70% of all protein-coding loci in mouse
(137) including those involved in three-dimensional patterning of the neural tube, regional brain morphogenesis,
stem cell expansion, proliferation and neurogenic and
gliogenic cell divisions, homeostatic and associated stress
responses, cell shape, motility and migration, brain feeding, metabolic and reward circuits, and progressive neuronal viability and synaptic maintenance as well as
plasticity (161).
Recently, it has been shown that siRNA-mediated
knockdown of antisense transcripts can alter the expression of the corresponding sense strand-derived mRNA,
although the effects are not predictable, with some senseantisense pairs showing concordant and others discordant regulation (137, 292). In addition, it appears that the
latter may not involve sense-antisense duplex formation,
nor the activation of the RNA interference pathway (80).
Indeed, these observations indicate that antisense RNAs
may regulate the expression of other transcripts in the
same locality, including those from the other strand, in
complex ways that are yet to be understood, but which
may share mechanistic features, such as effects on chromatin structure, in common with ncRNAs involved in
regulation of allelic expression at imprinted loci (see
below).
There are as yet very few well-described examples of
antisense RNAs affecting expression of genes in the nervous system, but this situation is likely to change radically
Physiol Rev • VOL
in the coming years. However, some instances are known,
although mechanisms remain obscure. In myelin-deficient
mice, there is tandem duplication of the myelin basic
protein (MBP) gene. The mutated upstream copy is transcribed within the brain as an antisense RNA that is
localized in the nucleus but is not polyadenylated (228). In
mutant mice, there is normal overall transcriptional activity of the MBP gene but a significant reduction in MBP
mRNA concentration in the cytoplasm. These observations indicate that either the processing or transport of
MBP mRNA to the cytoplasm is altered by the presence of
the antisense RNA.
In the nervous system of the snail Lymnaea stagnalis,
a nitric oxide synthase (NOS) pseudogene is transcribed
as an antisense RNA complementary to the NOS-encoding
mRNA (162). Suppression of NOS enzyme activity in cerebral giant cells is postulated to be caused by hybrid
arrest of translation mediated by the trans-acting antisense transcript transcribed by the NOS pseudogene.
With the use of a model of long-term memory formation,
it has been observed that posttraining expression of the
NOS pseudogene is transiently downregulated just before
transient upregulation of NOS mRNA and coincident with
the critical window for memory formation (145, 163).
These intriguing findings provide evidence that expression of a pseudogene can be regulated by a significant
behavioral stimulus. There is accumulating evidence that
gene duplication coupled to DNA inversion can produce
long sequence trans-acting antisense transcripts (160).
There is additional evidence that in both silkmoth and
Neurospora, core “circadian rhythm” clock genes are regulated by endogenous antisense transcripts (59, 101, 165).
Furthermore, susceptibility loci are present within the
disabled in schizophrenia 1 (DISC1) gene and in the
large antisense DISC2 RNA that is thought to modulate its
expression in both schizophrenia and in bipolar illness
(211, 212). DISC1 has been implicated in a complex spectrum of nervous system functions including cellular morphogenesis, neuroblast migration and axonal path finding,
and vesicular trafficking, and alterations of DISC1 functions during progressive stages of forebrain maturation
may underlie the developmental pathogenesis of these
selective neuropsychiatric syndromes (134).
B. Other Large Noncoding RNAs
There are also tens of thousands of mRNA-like
ncRNAs that are not antisense to known protein-coding
genes, although many of these loci also show transcription from both strands, similar to sense-antisense pairs at
protein-coding loci. These ncRNAs are transcribed by
RNA polymerase II, are polyadenylated, and often exhibit
alternate splicing (36, 46, 136). Many of these ncRNAs are
developmentally regulated and physiologically respon-
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Other small brain-specific trans-acting RNAs are the
dendritic BC200 RNA which arose from a monomeric Alu
element and is limited to the primate order, and the
analogous rodent dendritic BC1 RNA which was also
generated by retrotransposition (196, 227). Recent data
have suggested that BC1/BC200 may interact with FMRP
(130, 314, 315) and may also play a role in translational
inhibition (158, 294, 295). As suggested by Brosius (31),
we suspect that many so-called repetitive sequences derived from transposons may have in fact acquired functions. We further suggest that many of these functions are
elaborated via RNA, and may be intimately involved in
mammalian ontogeny, including brain development and
function.
NONCODING RNAS IN NEURAL DEVELOPMENT, FUNCTION, AND DISEASE
preferential enrichment within the nervous system. Many
ENOR loci contain host genes for miRNAs and
snoRNAs, show evidence of antisense transcription and
genomic imprinting, exhibit a predilection for brainselective expression, and display predominant nuclear
localization (88).
Recently, it has been reported that all but 2 of 49
regions of the human genome that are highly conserved
among mammals but show accelerated evolution since
our divergence from our common ancestor with the chimpanzee (“human accelerated regions” or HARs) are located outside of protein coding sequences and 24% are
adjacent to genes involved in neural development (240).
Moreover, the most rapidly evolving of these regions
HAR1 is part of the first exon of a 2.8 kb spliced ncRNA
termed HARF1 that is specifically expressed in CajalRetzius neurons in the developing human neocortex
(Fig. 1), as well as in ovary and testis. HARF1 is coexpressed with reelin, a protein that is critical for neuroblast
migration from paramedian stem cell generative zones
and for the specification of the layered structure of the
human cortex. In addition, there are two alternatively
spliced antisense transcripts HAR1Ra and HAR1Rb,
which also contain the HAR1 region in their first exon and
which are expressed in the brain and testis, respectively
(240). The temporal and spatial pattern of expression of
HAR1R suggests that it may have later developmental
effects to downregulate HAR1F by antisense-mediated
inhibition. Interestingly, reelin exhibits enhanced expres-
FIG. 1. Expression of the rapidly
evolving noncoding RNA HAR1F in the
developing brain. A: in situ hybridization on 19 gestational week (GW) coronal brain sections, illustrating expression of HAR1F in the hippocampal primordium (arrows) and dentate gyrus
(arrowheads). B: in situ hybridization
on 24 GW coronal brain sections, illustrating expression of HAR1F in the
cerebellar cortex (arrows in left panel)
and olivary complex (arrows in right
panel). HAR1F sense probe detects no
obvious signal. [From Pollard et al.
(240), with permission from Nature
Publishing Group.]
Physiol Rev • VOL
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sive, show particular abundance in the brain (123, 245),
and appear to be evolving rapidly (230). Unexpectedly,
there also appear to be large numbers of nonpolyadenylated large RNAs (46, 152), which have remained hidden
from view because of the use of oligo-dT for mRNA
purification and to prime reverse transcription in cDNA
cloning protocols. It is also possible, if not likely, that
many of these ncRNAs, as well as those derived from
introns (of both coding and noncoding transcripts), may
be subsequently processed to smaller RNAs that have
various functional properties and regulatory roles.
In Drosophila, large ncRNAs have been implicated in
a broad spectrum of developmental processes. These
ncRNAs display preferential expression during embryonic
development in general and within the nervous system in
particular (123). This unusual class of ncRNAs also functions prominently in dosage compensation and chromosome inactivation, forms of genomic imprinting that are
particularly important in neural development, adult nervous system function, and the etiology of neurodevelopmental and neuropsychiatric diseases (209, 239, 276). In
the Drosophila peripheral nervous system, the bereft RNA
plays important roles in extrasensory organ development
and in the adult maintenance of interommatidial bristles
of the eye (109).
A number of very long ncRNA species, termed
“macroRNAs” or long expressed noncoding regions
(ENORs), have recently been identified in mice (88).
ENOR loci, including ENOR 28 and ENOR 31, have the
capacity to give rise to multiple macroRNAs, all exhibiting
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MARK F. MEHLER AND JOHN S. MATTICK
C. Noncoding RNAs in Genomic Imprinting
Imprinted genes play seminal roles in brain development and adult functional activities. Moreover, misregulation of their patterns of gene expression can predispose
to a complex array of poorly understood neurodevelopmental and neuropsychiatric diseases (66, 67). Allele-specific genes display preferential expression within the nervous system and are often transcribed from larger
genomic regions encompassing multiple tandemly repeated miRNAs and C/D snoRNAs (67, 177, 262, 274).
Imprinted loci are capable of giving rise to a complex
amalgam of both unspliced as well as spliced longer
ncRNAs (58, 67, 88, 226, 274). Antisense RNAs to reciprocally imprinted neighboring protein-coding transcripts
are also found within or adjacent to imprinted loci (67,
274). Imprinted genes appear to modulate a broad spectrum of cellular processes within the nervous system
including intracellular signaling, RNA processing, growth
and cell cycle regulation, genome modifications, transcription factor actions, protein trafficking and processing, membrane-associated receptors, transporters and
structural proteins, and ncRNAs (67). The essential functions of imprinted genes throughout nervous system development and mature steady-state functioning are best
revealed by analysis of the breadth and diversity of neurological diseases associated with parent of origin effects
and disruptions in imprinted loci including schizophrenia,
attention-deficit hyperactivity disorder, autism, Tourette’s
syndrome, and bipolar disorder (reviewed in Refs. 66, 67).
Imprinted genes exhibit exquisite cell-specific patterns of expression within the brain, suggesting an ongoing role in modulating neural connectivity and activitydependent synaptic plasticity (reviewed in Ref. 67). The
Ube3a gene displays imprinted expression in specific
Physiol Rev • VOL
brain regions and cell types including mitral cells of the
olfactory bulb, Purkinje cells of the cerebellum, and the
hippocampus but displays biallelic expression in other
tissues and brain regions (5). Conversely, Igf2, Grb10,
and Zim1a are imprinted in many tissue types but exhibit
biallelic expression in the CNS (9, 69, 147). The Nnat gene
is imprinted predominantly in brain regions alone,
whereas Murr1 exhibits temporally restricted brain imprinting, and these expression profiles suggest the dynamic and complex regulation of genomic imprinting during brain development and mature functioning (133, 298).
Some imprinted genes occur in the introns of host
genes. For three of these microimprinted domains, the
imprinted and host genes are highly expressed in brain
particularly within the hippocampus (68, 298). These
structure-function interrelationships allow for potentially
complex interactions between genes and protein products. Several inserted imprinted genes (Nnat, Nap1l5,
Peg13, U2af-rs1) are paternally expressed (293). Other
imprinted genes in the CNS display reduced expression
from the silent allele, suggesting that brain-specific imprinting may be cell-selective or localized, and seemingly
minimal gene expression from the silent allele may represent the combined effects of regions of monoallelic and
biallelic expression (237, 238). There are also cell-specific profiles of imprinting in the CNS with Ras-Grf1
and monoallelic expression of Ube3a and the oppositely imprinted antisense Ube3a restricted to neurons,
whereas Ube3a and antisense Ube3a expression is biallelic in neural progenitor species and glial cells but
monoallelic in neurons (308). The maternally expressed
Nesp55 gene displays neuronal specificity (20); the paternally expressed Ndn, Nap1l5, and Peg13 exhibit
preferential neuronal specificity (68, 283); and the imprinted 5HT2a receptor gene is localized to both neurons and glia (138).
GTL2/MEG3 and RIAN represent two large imprinted ncRNAs preferentially expressed in the brains of
mice and humans (110, 305). Interestingly, a miRNA gene
cluster is present at the same locus as the mouse GTL2, a
spliced and maternally expressed ncRNA (262). In addition, a large number of tandemly repeated box C/D
snoRNAs are located downstream from GLT2 (67). Moreover, the box C/D snoRNAs M/HBII-13, M/HII-52, and
M/HBII-85, which are preferentially expressed in the nervous system, are clustered at a locus between the SNURFSNRPN and UBE3A genes that harbors several imprinted
genes implicated in the pathogenesis of Prader-Willi and
Angelman syndromes (67). H/MBII-52 is known to precisely modulate the A-I RNA editing and alternate splicing
of the 5HT (2C) mRNA and may thus represent a novel
subfamily of posttranscriptional regulators for proteincoding genes (67). The HBII-85 locus contains additional
box C/D snoRNA genes (HBII-436, HBII-437, HBII438A/B) within the same genomic interval, and this
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sion during primate evolution (214) and also undergoes
A-to-I RNA editing (175).
The Allen Brain Atlas (ABA) is a large-scale gene
expression study of the adult mouse brain using highthroughput RNA in situ hybridization to visualize the expression of over 20,000 transcripts at cellular resolution
(173). While this project was focused primarily on protein-coding genes, it also includes well over 1,000 probes
targeted against noncoding transcripts originating from
intergenic, intronic, and antisense regions, as well as
imprinted loci. Many of these transcripts are localized in
specific neuroanatomical regions, including several neocortical layers, as well as in the hippocampus, rostral
migratory stream, and olfactory bulb, which are primary
sites of neurogenesis, neuronal differentiation, and maturation in the mouse brain (T. Mercer, M. E. Dinger,
S. Sunkin, M. F. Mehler, and J. S. Mattick, unpublished
data).
NONCODING RNAS IN NEURAL DEVELOPMENT, FUNCTION, AND DISEASE
Physiol Rev • VOL
regions and neural cell subtypes (reviewed in Refs.
70, 150, 177, 253, 263).
VII. TRANSFER RNA, RIBOSOMAL RNA AND
DISEASES OF THE NERVOUS SYSTEM
In addition to their known roles in housekeeping
functions such as mRNA translation, transfer RNAs
(tRNAs) and ribosomal RNAs (rRNAs) have recently been
implicated in numerous distinct and specialized brain
functions during development as well as adult life as
assessed by the effects of mutations in these two classes
of ncRNAs in predisposing to a range of neurodevelopmental, neurodegenerative, and neuropsychiatric diseases (reviewed in Refs. 74, 75, 81). These mutations
predominantly affect the mitochondrial genome where
two-thirds of pathogenic mutations affect tRNAs that
themselves comprise only one-tenth of the entire mitochondrial genome.
Mitochondrial diseases exhibit several unique clinicopathological features including heteroplasmy, threshold effects, and mitotic and replicative segregation that
may define broader phenotypic links with these classes of
ncRNA alterations in disease pathogenesis and clinical
progression (74, 75). In general, mutations in both tRNAs
and rRNAs can cause a spectrum of neurological diseases
including chronic progressive external ophthalmoplegia
(CPEO), Kearn-Sayre syndrome (KSS; CPEO with retinal
degeneration), and MELAS (mitochondrial encephalopathy with stroke-like syndromes and migraine headaches)
and MERRF (myoclonus epilepsy, mitochondrial myopathy, cerebellar ataxia and far less frequently dementia,
peripheral neuropathy and hearing loss) syndromes (74,
75). MELAS syndrome and other tRNA-mediated diseases
are inextricably linked to a broad series of neuropsychiatric diseases including schizophrenia, personality disorders, major depressive disorders, anxiety disorders, psychosis, and delirium, and these clinical features may be
among the presenting symptom complexes that predate
by years the onset of classical neurological disorders (81).
tRNAs can more infrequently give rise to other neurological disorders including multisystem atrophy, Leigh’s
hereditary optic neuropathy (bilateral optic atrophy), and
neurosensory deafness (74, 75). MELAS and MERRF syndromes are usually caused by mutations in specific tRNAs
such as tRNALeu and tRNALys, respectively (74, 75).
MERRF has also been associated with mutations in
tRNAPhe (194), and mutations in tRNAHis can result in an
unusual syndrome that includes encephalitis, arterial
strokes, venous infarctions, and rhabdomyolysis (75). A
unique form of homoplasmic syndromic deafness can
result from mutations in the 12S rRNA or in tRNASer (UCN)
(179, 241, 278). In addition, the penetrance of the disease
may be enhanced by polymorphisms of the mitochon-
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snoRNA cluster is not expressed in the Prader-Willi syndrome that is associated with a large paternal deletion of
the entire imprinted domain (39, 72, 254).
Within the imprinted Dlk1-Gtl2 domain, many potential miRNAs are expressed downstream from a cluster of
snoRNAs (67, 262). These ncRNAs are only expressed
from the maternally inherited chromosome and are preferentially expressed in the nervous system. In this case, a
proximal intergenic differentially methylated region between the Dlk1 and the Gtl2 genes regulates imprinted
expression (281). Interestingly, targeted deletion of unmethylated sequences within this region results in the
repression of all maternally expressed ncRNAs and biallelic expression of all paternally expressed protein-coding
genes; the same deletion transmitted paternally has no
obvious effects (67, 183). Moreover, miR-127 and
miR-136 are processed from a large maternally expressed
Rtl1 antisense ncRNA (264). The Rtl1 gene is paternally
expressed and encodes a large open reading frame with
strong homology to the Gal and Pol retrotransposon domains (264, 313). Experimental observations strongly suggest that these two miRNAs negatively regulate Rtl1 expression through the mechanism of RNA interference due
to their perfect sequence complementarity (183). The profiles of sense/antisense gene organization coupled with
reciprocal imprinting of the miRNAs relative to their RNA
target gene suggest that small RNAs are involved in Rtl1
genomic imprinting. These overall findings suggest a link
between RNA interference, genomic imprinting, and retrotransposon silencing (67, 103).
Other imprinted miRNAs can inhibit RNA translation.
The Prader-Willi syndrome is a complex neurodevelopmental disorder presenting with mental retardation, hypothalamic insufficiency, and failure to thrive as a result
of three different mutations, deletion of paternally inherited 15q11–13, maternal uniparental disomy, and mutation
of the imprinting center (38). IPW is a neural imprinted
gene within the Prader-Willi locus that represents a
spliced and polyadenylated ncRNA (301). ZNF127 and
ZNF127 antisense transcripts are encoded at the IPW
locus and are expressed predominantly in brain from
the antisense strand (132). Angelman syndrome is
caused by three reciprocal mutations to Prader-Willi
syndrome and is represented pathologically by cortical
atrophy, cerebellar dysmyelination, and Purkinje cell
loss (38). Patients with Williams syndrome exhibit profound mental retardation and microcephaly caused by
maternal deletion of a region of chromosome 7q11.23,
although it is not yet certain whether the syndrome is
caused by disruption of imprinted genes (7, 235). These
cumulative observations demonstrate that ncRNAs are
prominently represented within imprinted loci and
clearly have a spectrum of essential functions in the
process of genomic imprinting and the selectivity of
allelic expression within developing and mature brain
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MARK F. MEHLER AND JOHN S. MATTICK
VIII. CYTOPLASMIC NONCODING RNA
IN SYNAPTIC SPECIALIZATION
AND FUNCTION
Several distinct classes of ncRNAs are required for
axodendritic process outgrowth and maturation and synaptogenesis. These same ncRNA species promote mRNA
axonal transport, synaptic targeting, and local protein
synthesis within “activated synapses” and thus function as
essential molecular constituents mediating synaptic plasticity (reviewed in Ref. 127). The FMRP is an RNA binding
protein that may play a seminal role in synaptic plasticity
and synapse-selective protein translation. In the fragile-X
syndrome, genetic alterations of FMRP cause a characteristic neurodevelopmental disorder consisting of mental
retardation, autism, anxiety disorders, and epilepsy or a
neurodegenerative syndrome during the “premutation”
phase (see below). The FMRP ribonucleoprotein complex(es) may include numerous other molecular species
such as FXR1P/2P, nucleolin, YB1/p50, Pur␣, staufen,
IMP1 (RNA transport factor), and kinesin 5 (41, 42, 135,
243). In addition, Pur␣ links the cytoplasmic mouse and
human ncRNAs BC1/200 to microtubules, and this dynamic ribonucleoprotein subcomplex is actively transported to dendrites to participate in the process of synaptic tagging (227), defined as specific information hubs
of coincident electrical and molecular activities essential
to encode synapse-specific information for precise signal
propagation within activated neural networks (130, 307).
Pur␣ further interacts with two additional ncRNAs, TAR
RNA element of HIV1 and signal recognition particle
(SRP) RNA, and this association enhances DNA replication and transcription and membrane translocation (48,
89, 130, 287). YB1 regulates alternate splicing, transcription and translation, DNA repair, and stress responses
(42, 156). Moreover, YB1 interacts with MECP2, the gene
mutated in the neurodevelopmental disorder Rett’s syndrome (X-linked mental retardation, psychosis, autism,
Physiol Rev • VOL
Angelman’s syndrome, and neonatal encephalopathy)
(312). MECP2 is known to orchestrate methylation-dependent transcriptional repression, which is probably RNA
directed (25), and more recently has been implicated in
alternate RNA splicing (312).
Neuronal stimulation increases intracellular calcium
levels and activates calpain, which, in turn, liberates dicer
and elF2c at postsynaptic densities (188). These processes act on miRNA precursors and sense/antisense RNA
pairs to modulate stabilization and translational of local
mRNAs (188, 229, 260). Synaptic protein synthesis is regulated by activity-dependent downregulation of the RISC
pathway and proteasomal-mediated degradation (12).
miRNA target sequences are present in the 3⬘-UTRs of the
kinesin and the calcium-calmodulin protein kinase II
(CaMKII) genes and miR-280 and miR-289 can interact
with the 3⬘-UTRs of the CaMKII and other genes that are
targets of RISC-mediated translational silencing (12).
Specific forms of synaptic plasticity also act in concert with FMRP-containing ribonucleoprotein complexes
to fine-tune the kinetics of local protein synthesis (120,
127). Additional classes of ncRNAs including rRNAs and
tRNAs are also present within discrete dendritic domains
and contribute to the modulation of RNA translation and
signal integration from multiple synaptic inputs (148, 153,
285). Local protein synthesis promotes retrograde messenger trafficking from the synapse to the cell body to
activate mRNA synthesis and to concurrently “mark” activated synapses (19, 125). Thus distinct profiles of synaptic activation give rise to unique molecular signatures
and contribute to the speed and efficacy of intracellular
transport and utilization processes embedded within a
multi-tiered rapid and reversible regulatory cascade including differential utilization of multiple ncRNA subclasses. BC1 is also intimately involved in neural development, somadendritic levels of BC1 are reversibly modulated by neuronal activity, and BC1 may cooperate with
FMRP to regulate local dendritic translation initiation
(32, 219, 314, 315).
RNA-mediated mechanisms may also be involved in
both normal and pathological features of prion proteins. It
is now well established that certain spongiform encephalopathies are orchestrated by transmissible proteinaceous
agents termed prions (PrPSc) that undergo self-propagation by promoting conformational changes in the normal
cellular (PrP) species (51). Recent studies indicate that
only single-stranded RNA, but not RNA/DNA homo- or
heterodimers, has the potential to stimulate PrPSc elaboration and propagation in isolated brain preparations (71).
These observations suggest that host-encoded RNA species may be involved in the etiology of a spectrum of
diverse prion diseases as well as novel types of normal
neurological functions. Interestingly, a neuronal member
of the cytoplasmic polyadenylation element binding protein (CPEB) family that regulates mRNA translation also
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drial ND protein-coding gene in association with the
tRNASer (UCN) mutation (84, 85). Moreover, pseudouridylation of tRNAs by a homozygous missense mutation of
the gene encoding pseudouridine synthase 1 can give rise
to an autosomal recessive mitochondrial myopathy (33).
Interestingly, specific alterations in the levels of expression of specific tRNAs (tRNAVal, tRNAAsn, tRNALys) and
rRNAs (5.8S and 5S rRNAs) have been observed in selective regions of the aging human brain predisposed to
undergoing degenerative changes in associated with Alzheimer’s disease and its antecedent, minimal cognitive
impairment, with the profiles of these ncRNA changes
predictive of the two related syndromes (76). Furthermore, motor neuron disease has recently been linked to
mutations in tRNAIle (29).
NONCODING RNAS IN NEURAL DEVELOPMENT, FUNCTION, AND DISEASE
IX. RNA-MEDIATED MECHANISMS
UNDERLYING SPECIFIC
NEUROLOGICAL DISEASES
Neurodevelopmental and neurodegenerative diseases
associated with trinucleotide repeat expansion may be
caused by complex combinations of abnormal RNAmediated transcriptional silencing, trans-dominant RNAmediated pathogenic mechanisms, and ncRNA-mediated
RNA interference (reviewed in Refs. 90, 92). Fragile-X
syndrome results from dramatically expanded (⬎200)
CGG repeats in the 5⬘-UTR of the Fmr1 gene and a loss of
function mechanism with complete transcriptional silencing (108). In contrast, smaller (60 –200) trinucleotide repeat expansions at the FMRP gene locus are called “premutations” but have recently been linked to a complex
neurodegenerative disease called fragile-X tremor/ataxia
syndrome (FXTAS) associated with tremor, cerebellar
ataxia, Parkinson’s disease, dementia, cognitive deterioration, peripheral neuropathy, proximal muscle weakness, autonomic system dysfunction, and multisystem atrophy (289). In FXTAS there is a pathological increase in
Fmr1 transcripts and reduced translational efficiency
with sequestration and misfolding of cellular proteins,
suggesting an RNA-mediated toxic gain-of-function mechanism (284, 303).
Physiol Rev • VOL
Interestingly, the FMRP gene premutation is also associated with a discrete developmental disorder characterized by mental retardation, autism, and learning disorders, further expanding our view of the complexity of
RNA-mediated nervous system dysfunction and the role
of critical developmental periods in mediating pathogenesis (289). The premutation neurodegenerative disease
variant exhibits striking gene dosage- and repeat lengthdependent clinicopathological effects (128). Furthermore,
an rCGG-repeat binding protein (rCGGBP) has recently
been identified, and sequestration of specific rCGGBPs
has been linked to pathological neuronal death (90). A
related syndrome, fragile-X syndrome E, is caused by
CCG repeats in the 5⬘-UTR of the FMRP2 gene with
associated hypermethylation of CpG islands and transcriptional silencing (107, 155, 217). FMRP2 plays important roles in nervous system development, neural cell
differentiation, sensory perception, synaptic plasticity,
and memory formation (106).
Myotonic dystrophy (MD) is predominantly a muscle
and multisystem disorder but exists in two forms with
different profiles of nervous system dysfunction, including DM1 with mental retardation, executive dysfunction,
and visuospatial and memory deficits and DM2 with predominant frontal lobe working memory and executive
dysfunction (62). DM1 exhibits CTG expansion within the
3⬘-UTR of the dystrophia myotonica protein kinase
(DMPK), whereas DM2 is coupled to CCTG expansion in
intron 1 of the zinc finger protein ZNF9 (30, 87, 184, 193,
244). Mutant RNAs in DM1 and DM2 contribute to disease
pathogenesis through different degrees and types of repeat length expansion and by differential interactions
with several RNA-binding proteins of the muscleblind-like
(MBNL) family (126, 231). These abnormal interactions
result in selective nuclear sequestration of MBNL proteins
and interference with their roles as modulators of alternate splicing. Several deregulated neuronal transcripts
with splicing defects have been identified in DM1, including tau, amyloid precursor protein, and the N-methyl-Daspartate (NMDA) NR1 receptor, and these abnormal molecular profiles may contribute to disease manifestations
and to the complex phenotypes seen in MD (126). These
overall findings suggest the effects of a trans-dominant
RNA-mediated pathogenic mechanism.
RNA-mediated motor neuron degeneration in lowmolecular-weight neurofilament (NF-L) mutant mice is
mediated by a major RNA instability determinant in NF-L
(34, 225). p190 RhoGEF is a neuron-enriched guanine
exchange factor that binds to the NF-L destabilizing element, the 3⬘-UTR of NF-L mRNA, and may thus link
neurofilament expression to pathways modulating neuronal homeostasis (34). BC1 and the low-molecular-weight
form of NF-L mRNA exhibit mutually exclusive binding to
p190 RhoGEF, suggesting a potential role for BC1 in the
etiology of motor neuron disease (93). Interestingly, neu-
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exhibits prionlike properties (270). In contrast to other
CPEB family members, Aplysia neuronal CPEB possesses an NH2-terminal extension that shares molecular
and biophysical properties with prion species (65). Moreover, full-length CPEB undergoes epigenetically driven
changes in conformational properties during conversion
to the active state that are self-perpetuating and display
the greatest capacity to promote CPEB-mediated local
mRNA translation. A brain-specific form of CREB in mice
(mCREB-3) differs from other mammalian CREB isoforms in that it contains an additional 2,500 bp of 3⬘-UTR
and a smaller NH2 terminus with a Q-rich domain postulated to be capable of forming prionlike switches (65).
In Aplysia, neurotransmitter-mediated enhancement of
CPEB levels promotes long-term synapse-selective modifications through the independent properties of spatial
restriction (synapse specificity) as well as persistence
(duration) (269, 270). These observations suggest that
selective RNA-associated prionlike properties of CPEB
may facilitate the activation of dormant mRNA initially
elaborated within the cell soma and distributed globally
but selectively translated locally within activated synapses (16). These epigenetically mediated plasticity mechanisms may underlie the long-term changes in synaptic
strength associated with memory storage as well as other
dynamic neural state transitions such as cellular differentiation and even transcription.
813
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MARK F. MEHLER AND JOHN S. MATTICK
nonsense mediated RNA decay (17, 60). Progranulin is
involved in gender-specific hypothalamic development
and in numerous other nervous system developmental
events, and overexpression is associated with various
types of high-grade and invasive malignancies including
glioblastoma multiforme (60, 64, 111). Interestingly,
BC200 RNA is dramatically downregulated in post mortem brains of Alzheimer’s disease patients (189). These
latter findings implicate diverse RNA-associated mechanisms in the pathogenesis of neurodegenerative diseases.
Spinocerebellar ataxias (SCAs) may also result from
distinct RNA-mediated pathological processes. SCA8 is
caused by CTG expansion of the 3⬘-UTR of an untranslated antisense RNA with significant overlap with the
Kelch-like 1 (KLHL1) gene (159, 224). The gene mutation
may cause the clinicopathological manifestations of this
neurodegenerative disease by misregulation of the KLHL1
actin-binding protein or by the toxic consequences of the
expanded RNA in ways similar to DM (92, 221). Interest-
FIG. 2. The complexity of RNA transactions in the nervous system. White and pale blue boxes indicate constitutively spliced exonic
non-protein-coding and protein-coding sequences, respectively. Pink and dark blue boxes indicate alternatively spliced exonic non-protein-coding
and protein-coding sequences, respectively. Green octagons indicate snoRNAs, and purple diamonds indicate miRNAs. Solid lines indicate known
interactions and pathways. Dotted lines indicate potential interactions and pathways.
Physiol Rev • VOL
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ropathological examination in the setting of superoxide
dismutase 1 (SOD1) mutations has revealed abnormal
protein aggregates containing mutant SOD1, NF-L, and
p190RhoGEF (181, 182). Motor neuron disease-associated
mutations in SOD1 result in differential splicing of peripherin pre-mRNA and the generation of neurotoxic forms of
peripherin (248). Frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17) is also
characterized by alternate splicing of the microtubuleassociated protein tau (MAPT) gene and altered spatiotemporal expression of specific differentially spliced
MAPT exon 10-associated isoforms, suggesting a potential
role in pathogenesis of abnormally activated RNA binding
proteins perhaps in the context of alterations of specific
ncRNAs (14, 63, 90). A different form of FTD-17 has
recently been linked to a series of diverse mutations in the
progranulin gene including alternate splicing, intron retention, and production of mutant mRNA transcripts that
predispose to nuclear retention and RNA degradation or
NONCODING RNAS IN NEURAL DEVELOPMENT, FUNCTION, AND DISEASE
X. CONCLUSION
The list of verified targets of RNA editing and of the
number and functional subclasses of noncoding RNAs
involved in the nervous system has steadily increased and
likely still represents only a small fraction of the total
transcriptome devoted to RNA-mediated mechanisms underlying the ontogeny and functional complexity of mammalian brain functions in health and disease. We hope
that this review raises awareness of the central roles that
RNA editing, RNA modification, and the enormous numbers of both small and large noncoding RNAs, and the
complex regulatory networks in which they participate,
play in neural network development, steady-state function, plasticity and metaplasticity, dysfunction, degeneration, and regeneration, as well as stimulate the design of
new experiments and the search for ncRNA candidates in
genetic studies. It has become increasingly apparent that
the vast majority of the human genome is devoted to
RNA-mediated regulatory circuitry (199, 203) and that the
traditional view that most genes and genetic information
are expressed as proteins, which is largely true in the
prokaryotes but not in the complex eukaryotes, has led to
a fundamental misunderstanding of the nature of the genetic programming of human differentiation and development. We suggest that this is especially pertinent in the
human nervous system, where the evolutionary requirements of brain form and function, neural network integrity, and bioenergetic conservation mandate that RNA
Physiol Rev • VOL
transactions be most versatile, multilayered, and nuanced
(Fig. 2). We also suggest that brain development, brain
plasticity, and the formation of the information networks
underlying learning, memory, and complex cognitive
functions are intimately connected to environmentally
driven recoding of the transcriptome and possibly even
the genome itself in response to experience.
ACKNOWLEDGMENTS
We thank Marcel Dinger, Ryan Taft, and Irfan Qureshi for
helpful comments on the manuscript.
Addresses for reprint requests and other correspondence:
M. F. Mehler, Institute for Brain Disorders and Neural Regeneration, Depts. of Neurology, Neuroscience, and Psychiatry and
Behavioral Sciences, Einstein Cancer Center and Rose F.
Kennedy Center for Research in Mental Retardation and Developmental Disabilities, Albert Einstein College of Medicine,
Bronx, NY 10461 (e-mail: [email protected]); J. S. Mattick,
ARC Special Research Centre for Functional and Applied
Genomics, Institute for Molecular Bioscience, Univ. of Queensland, St. Lucia, QLD 4072, Australia (e-mail: j.mattick
@imb.uq.edu.au).
GRANTS
This work was supported by grants from the National
Institutes of Health (NS-38902, MH-66290, and HD-01799) and
the F. M. Kirby, the Skirball, the Rosanne H. Silbermann and the
Roslyn and Leslie Goldstein Foundations (to. M. F. Mehler), and
by the Australian Research Council (Federation Fellowship
Grant FF0561986), the Queensland State Government, and the
University of Queensland (to J. S. Mattick).
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