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Curr Psychiatry Rep (2010) 12:154–161
DOI 10.1007/s11920-010-0102-1
Small RNA-Mediated Gene Regulation
in Neurodevelopmental Disorders
Abrar Qurashi & Peng Jin
Published online: 19 March 2010
# Springer Science+Business Media, LLC 2010
Abstract An expanding assortment of small, noncoding
RNAs identified in the nervous system suggests a strong
connection between their combinatorial regulatory potential
and the complexity of the nervous system. Misregulation
of these small regulatory RNAs could contribute to the
abnormalities in brain development that are associated with
neurodevelopmental disorders. Here we give an overview
of the diversity and unexpected abundance of small RNAs,
as well as specific examples that illustrate their functional
significance in neurodevelopmental disorders. We also
discuss an intriguing, albeit elusive area of study: the
potential impact of newly discovered classes of small
RNAs in the nervous system.
Keywords Small RNA . microRNA . Neurodevelopmental
disorder . Fragile X syndrome . Rett syndrome .
DiGeorge syndrome . Down syndrome
Introduction
The perception of RNA solely as a messenger between
DNA and protein was changed radically when RNA was
found to catalyze its own replication and the synthesis of
A. Qurashi
Department of Human Genetics,
Emory University School of Medicine,
Atlanta, GA, USA
e-mail: [email protected]
P. Jin (*)
Department of Human Genetics,
Emory University School of Medicine,
615 Michael Street, Suite 301,
Atlanta, GA 30322, USA
e-mail: [email protected]
other RNA molecules. This led to the idea that RNA might
have been the first genetic material on earth, giving rise to
the concept of the “RNA world”; it also suggested that
RNA could play a more active role in gene expression than
previously thought. Since the discovery of the first small
RNAs, lin-4 and let-7, and their ability to trigger silencing
of a complementary messenger RNA sequence, a new era
of RNA function in gene regulation has opened up [1].
With analyses of the human genome showing that 98% of
the transcriptional output of the genome does not translate
into proteins, noncoding RNA has taken on more importance for humans, with similar findings for mice and other
eukaryotes [2–4]. After the initial discovery of lin-4 and
let-7, the number of known small RNAs mushroomed, and
they have been described as the “dark matter” of the cell.
At present, much scientific interest is focused on the small
noncoding RNAs because they target both chromatin and
transcripts, thereby keeping both the genome and the
transcriptome under extensive surveillance [1]. They are
involved in a range of physiologic functions, such as
developmental transitions and neuronal patterning, apoptosis,
fat metabolism, and regulation of hematopoietic lineage
differentiation [1, 5–9•]. Although the known small RNAs
act to regulate gene expression, they do differ widely in
terms of their size, structural and/or sequence features,
biogenesis mechanism, type of protein-binding partners,
and the manner in which they function. Based on these
criteria, they are sorted into three classes: microRNAs
(miRNAs), endogenous small interfering RNAs (esiRNAs),
and Piwi-interacting RNAs (piRNAs) [1, 9•] (Fig. 1).
The human nervous system is sophisticated in its unique
ability to achieve higher-order cognitive functions, including learning and memory. This functional property is in turn
orchestrated by a complex set of multilayered developmental
mechanisms. Alterations to specific components of these
Curr Psychiatry Rep (2010) 12:154–161
155
+
+
–
Transcription
+
+
–
–
+
–
Transcription
–
Transcription
pri-miRNA
Drosha
AAAA
m 7G
DGCR8
esiRNA precursors
pre-miRNA
piRNA precursors
Exportin-5/
RanGTP
cisdsRNA
Hairpin
transdsRNA
Nucleus
Export
Export
Export
Cytoplasm
Dicer
Primary
processing
AGO1–4
TRBP or PACT
Miwi2
Dicer
TRBP
Miwi2
Miwi
Ping pong
cycle
Target
p
Ago2
Mili
AAAAA
A
esiRNA
B
Fig. 1 Biogenesis of small regulatory RNAs in mammals. a Genes
encoding microRNAs (miRNAs) are initially transcribed by RNA
polymerase II or III to generate the primary miRNA transcripts
(pri-miRNA) within the nucleus. The stem loop structure of the primiRNA is recognized and cleaved on both strands by a microprocessor
complex, which consists of the nuclear RNase III enzyme Drosha and an
RNA-binding protein, DGCR8, to yield a precursor miRNA (premiRNA) 60 to 70 nucleotides in length. The pre-miRNA is then exported
from the nucleus through a nuclear pore by exportin-5 in a Ran-GTPdependent manner and processed in the cytoplasm by the RNase III
Dicer, TRBP (HIV-1 TAR RNA-binding protein). Sliced RNA strands
are further unwound by an RNA helicase. One strand of the miRNA/
miRNA* or siRNA duplex (the antisense, or guide strand) is then
preferentially incorporated into the RNA-induced silencing complex (or
miRNA-containing ribonucleoprotein complex [miRNP] for miRNAs)
and will guide the miRNP to a target mRNA in a sequence-specific
C
manner. b The precursors of Piwi-interacting RNA (piRNA) are derived
from intergenic repetitive elements, transposons, or large piRNA
clusters. piRNA precursors are transported via an unknown mechanism
to the cytoplasm. Once in the cytoplasm, they are associated with Piwi
subfamily proteins. After primary processing, these precursors interact
with Piwi proteins. Both Miwi and Mili are localized in the cytoplasm.
The proteins involved in primary processing remain elusive. Mili
introduces a cleavage in the precursor-generating 5′ end of piRNA,
which is subsequently accepted by Miwi2. Miwi2 also cleaves the
opposite strand precursor, generating the 5′ end of the piRNA that
subsequently binds to Mili. The nuclease that creates the 3′ end of
piRNA has yet to be determined. c Endogenous siRNA (esiRNA)
precursors are derived from repetitive sequences, either sense–antisense
pairs or long-stem loop structures. Their biogenesis is mediated by
Dicer and Argonaute 2 protein (AGO2)
156
developmental stages and maturational processes lead to
a broad spectrum of neurodevelopmental disorders that
predispose people to neuropsychiatric disorders, including
intellectual disability, autism, attention-deficit/hyperactivity
disorder, and epilepsy [10, 11]. Despite their unique etiology
and clinical presentation, most neurodevelopmental disorders
share a common trait: disease onset occurs during periods of
ongoing maturation and development. Importantly, a mixture
of genetic mutations and environmental and epigenetic
factors seems to impact neurodevelopment, leading to
nervous system dysfunction [10, 11].
Small regulatory RNAs, particularly miRNAs, are dynamically regulated in neurogenesis and brain development
[1, 10]. It is now well-established that small RNAs,
particularly miRNAs, show distinct expression patterns
during mammalian brain development and are considered
to be key regulators of the nervous system, at least in lower
organisms [1, 10]. Tightly controlled miRNA expression is
required for proper neurodevelopment; conversely, specific
miRNA dysregulation is likely linked to the pathogenesis of
neurological disorders [1, 10, 11]. In this review, we focus
on our understanding of the functional impact of small
regulatory RNAs on brain development in general, as well as
in several well-defined genetic disorders.
Small Regulatory RNAs in the Genome
There are at least three known classes of small regulatory
RNAs in mammalian genomes: miRNAs, esiRNAs, and
piRNAs. They are classified based on their biogenesis
mechanism and protein-binding partners, as well as their
structural and/or sequence features [9•]
miRNAs: Biogenesis and Mode of Action
miRNAs are endogenous 18- to 25-nucleotide (nt), singlestranded, noncoding regulatory RNAs that are known to
regulate the translation of target mRNA molecules in a
sequence-specific manner [1, 8, 9•, 10, 11]. The biogenesis
of miRNAs involves enzymatic machinery that is wellconserved across animals and plants [8, 10]. Typically,
RNA polymerase II mediates the transcription of most
miRNA genes to generate the primary miRNAs (primiRNAs), which range from hundreds to thousands of
nucleotides in length and contain one or more extended
hairpin structures [1, 9•]. In the nucleus, a complex
containing both the RNase III endonuclease Drosha and
DiGeorge syndrome critical region gene 8 (DGCR8)
cleaves both strands near the base of the primary stemloop and yields the approximately 65-nt or longer precursor
miRNA (pre-miRNA) [1, 9•]. Recent studies indicate that
the processing of pri-miRNA may be coupled with
Curr Psychiatry Rep (2010) 12:154–161
transcription. In this case, Drosha cleaves the pri-miRNA
hairpin to yield pre-miRNA; the rest of the transcript
undergoes pre-miRNA splicing and produces mature
mRNA for protein synthesis [1, 9•]. Apart from canonical
intronic miRNAs, a small group of miRNAs called mirtrons
(intronic small RNAs) has been discovered in the introns of
flies and mammals. These small RNAs are derived from
small introns that resemble pre-miRNAs and can bypass the
Drosha-processing step [1, 9•]. Following nuclear processing, pre-miRNAs are transported out of the nucleus by
exportin-5/RanGTP and are further processed by Dicer,
a double-stranded RNA (dsRNA)-specific endonuclease,
along with a dsRNA-binding protein and TRBP (HIV-1
TAR RNA-binding protein) to produce an approximately
22-nt RNA duplex. One strand of the approximately 22-nt
RNA duplex is then preferentially incorporated into the
effector complex, the RNA-induced silencing complex
(RISC), as a mature miRNA (the guide strand or miRNA),
whereas the other strand (the sense, or passenger strand) is
degraded [1, 9•]. The RISC is a large, heterogeneous,
multiprotein complex whose key components include
Dicer, TRBP, and Argonaute 2 protein (AGO2). The RISC
uses the guide RNA to find complementary mRNA
sequences via base-pairing with (in many cases) the 3′untranslated region (3′-UTR) of target mRNAs, which leads
to post-transcriptional gene silencing via inhibition of
translation initiation or elongation [1, 9•]. miRNA could
also negatively regulate protein expression through targeting of mRNA coding regions [1, 9•].
Piwi-Interacting RNAs and Endogenous Small Interfering
RNAs
piRNAs were first discovered through small RNA profiling
of Drosophila melanogaster [5]. High-throughput sequencing uncovered a subset of endogenous, germ cell-specific
small RNAs (24–31 nt) that were clearly distinct from
miRNAs in size. Most of this longer species corresponded
to intergenic repetitive elements, including retrotransposons;
they were therefore termed repeat-associated small interfering
RNAs (rasiRNAs). Earlier studies in D. melanogaster had
suggested that small RNAs that correspond to retrotransposons might be involved in the silencing of transposable
elements [5, 9•]. The physical interaction of rasiRNAs with
Piwi proteins was revealed by immunoprecipitation of Piwi
complexes, including the third member of this subfamily,
AGO3. The Piwi subfamily proteins in mice (Miwi2, Mili,
and Miwi) as well as in zebrafish (Ziwi and Zili) were also
found to be associated with small RNAs that resemble
rasiRNAs. These small (24–31 nt) RNAs were termed
piRNAs and correspond to transposon sequences, implying
that they also function in silencing selfish DNA elements
[5, 9•]. Although the biogenesis of piRNAs has not been
Curr Psychiatry Rep (2010) 12:154–161
well-characterized, current studies suggest that it requires
Piwi proteins, but, unlike miRNAs and siRNAs, they are
neither Drosha- nor Dicer-dependent. piRNAs are likely
produced from long, single-stranded RNA precursors that are
transcribed from intergenic repetitive elements, transposons,
or large piRNA clusters by yet-to-be-identified endonucleases
[9•, 12••, 13••].
Another recently discovered class of small RNAs
expressed more ubiquitously is that of esiRNAs, which
are about 21 nt in length. The biogenesis of esiRNAs
initiates with bidirectional transcription or the transcription
of an inverted repeat [9•, 11]. The resulting dsRNA or the
hairpin RNA precursor is then processed by the components of the miRNA pathway [9•, 11].
miRNAs in Neurodevelopment: A General View
Although many of the brain-specific miRNAs have been
identified, the functions of only a few are known. Nonetheless, the effects of miRNA-mediated modulation on gene
expression during normal development, differentiation, and
homeostasis, as well as related pathological conditions, are
widely accepted [1, 8, 14, 15].
Strong evidence for the biological roles of miRNAs in
neural development emerged from their identification
within the homeobox (HOX) gene clusters. Hox genes
function in patterning the anterior-posterior axis of the
central nervous system, and several miRNA genes located
within the Hox gene clusters provide control over development [1, 16]. Deletion of both maternal and zygotic Dicer
in zebrafish and Dicer-deficient mice supports a role for
miRNAs during segmentation and differentiation or maintenance of tissue identity [1, 8, 10, 17, 18]. However, the
importance of miRNAs in the establishment of tissue fate
came from studies in Drosophila, in which the patterned
expression of many miRNAs was seen at the onset of
zygotic transcription in early embryos [1]. Similarly, studies
in Caenorhabditis elegans have shown that the cell fate
decision between two taste receptor neurons and maintenance of their identity arises via a complex regulatory
network of interactions between two miRNAs, miR-273
and lsy-6, and their transcription factor targets [1, 6]. As
neurons undergo differentiation, changes in the expression
of a small number of miRNAs (eg, increased expression of
miR-124 and miR-9) do occur [1, 8, 10]. A role for miR124 in neurogenesis has been established definitively in
vivo, revealing its critical role in neuronal differentiation
from neural precursor cells [1, 8, 10].
miRNAs continue to be expressed or enriched in adult
neurons, particularly at dendrites, where they contribute to
local translational control in an activity-dependent manner
to sculpt the translational profile. The implications of this in
157
brain development and plasticity become clear from rat
hippocampus synapses, where miRNA-134 is present at
synaptic sites and maintains the translational silencing of
the Limkinase1 (LimK1) mRNA until a synaptic input
overrides the silencing [19]. LimK1 regulates actin filament
dynamics and has important functions in dendrite and spine
development and maintenance. Another study demonstrated
that miR-138 controls dendritic spine morphogenesis;
likewise, miR-132 targets and represses P250GAP, a Rho/
Rac regulator. Ashraf and colleagues [20] have shown that
protein synthesis of α-calcium/calmodulin-dependent protein
kinase II (α-CaMKII) is controlled by the RISC component
Armitage, which is co-localized with α-CaMKII in synaptic
punctate. The dsRNA-binding proteins Staufen and kinesin
heavy chain are under similar control. When Armitage is
degraded in response to neural activity, α-CaMKII mRNA
translation is increased [20]. Combined, these studies suggest
that the miRNA pathway is involved in the regulation of
local protein synthesis, which is in turn required for the
neuronal construction and plasticity that ultimately affects
higher brain functions (eg, learning and memory) [8].
miRNAs in Neurodevelopmental Disorders
Given the role of miRNA in neuronal development and the
control of neuronal functional elements, many researchers
have sought a link between miRNAs and neurodevelopmental diseases. Indeed, the roles of specific miRNAs have
been explored in several neurodevelopmental diseases (eg,
fragile X syndrome [FXS], Rett syndrome, DiGeorge syndrome [DGS], and Down syndrome [DS]).
Fragile X Syndrome
FXS, one of the most common forms of inherited mental
impairment, was the first genetic disorder linked to the
miRNA pathway [7, 21]. Clinical presentations of FXS
include characteristic physical and learning disabilities, as
well as more severe cognitive and intellectual disabilities. In
1991, positional cloning of the fragile X mental retardation-1
(FMR1) gene revealed the molecular basis of FXS; the
syndrome is associated with a massive unstable CGG
trinucleotide repeat expansion within the gene’s 5′-UTR.
The disease becomes clinically manifest as the gene is
passed from generation to generation and the CGG repeat in
the 5′-UTR of an Fmr1 allele expands, shutting down
production of the FMR1 gene product, fragile X mental
retardation protein (FMRP) [7, 21].
The association of FMRP with the RISC and miRNAs
themselves can be drawn through various biochemical and
genetic interaction studies. In flies, dFMRP biochemically
interacts with functional RISC proteins, including dAgo1,
158
dAgo2, and Dicer [8, 11, 21]. Genetically, dFmr1 dominantly interacts with dAgo1 in both dFmr1 overexpression
and loss-of-function models. Pickpocket1 (PPK1) was
found to be an mRNA target of dFMRP, and the expression
of PPK1 seems to be regulated by both dFMRP and dAgo2
[22]. Other studies supporting the involvement of FMRP in
miRNA/RNA interference function come from the identification of P body-like granules in Drosophila neurons that
function together with Me31B in an Argonaute-dependent
translational repression [23]. Interestingly, FMRP itself can
associate with and act as an acceptor protein for Dicerderived miRNAs and, importantly, facilitate the assembly
of miRNAs on specific target RNA sequences. In the adult
mouse brain, Dicer and eIF2c2 (the mouse homologue of
AGO1) also have been found to interact with FMRP at
postsynaptic densities [24]. Presumably, this interaction
works to regulate translation of target mRNAs in an
activity-dependent manner. Based on these findings, it has
been proposed that RISC components, including Argonaute
and Dicer, could interact with FMRP and use the loaded
guide miRNA(s) to interact with target sequences within the
3′-UTR of mRNA bound to FMRP and thereby suppress
translation. In this model, FMRP facilitates the interaction
between miRNAs and their target mRNA sequences,
ensuring proper targeting of guide miRNA-RISC within
the 3′-UTRs and proper translational suppression.
That FMRP is associated with Dicer, miRNAs, and
specific mRNA targets raised the question of whether
FMRP could be associated with specific miRNAs and
modulate their processing. Although whether specific
miRNAs are associated with FMRP in mammals remains
to be determined, in flies, dFMRP is required for proper
processing of pre-miR-124a; loss of dFmr1 leads to a
reduced level of mature miR-124a and an increased level of
pre-miR-124a [25]. These results suggest a modulatory role
for dFMRP to maintain proper levels of miRNAs during
neuronal development. Furthermore, in fly ovaries, bantam
miRNA (bantam) is associated with dFMRP physically and
genetically for the proper maintenance of germline stem
cells, thus supporting the notion that the FMRP-mediated
translational pathway functions through specific miRNAs
to control stem cell regulation [26, 27].
Rett Syndrome
Rett syndrome, an X-linked progressive neurodevelopmental
disorder associated with mental retardation, is believed to
result from loss of methyl CpG binding protein-2 (MeCP2) in
neurons [28, 29]. In a typical case, MeCP2 expression
increases as neurons differentiate prior to synaptogenesis.
MeCP2 has been shown to function as a transcriptional
repressor complex [29, 30]. More recently, MeCP2 was
shown to function as a transcriptional activator at certain loci
Curr Psychiatry Rep (2010) 12:154–161
[30]. The epigenetic regulation mediated by MeCP2 is also
provided through the transcription of noncoding RNA
elements such as miRNA. In the absence of MeCP2, some
miRNAs may display increased expression, which may
result in a negative effect on the translation of mRNAs
targeted by that particular miRNA. Importantly, in postnatally cultured rat neurons, miR-132 directly represses the
expression of MeCP2. MeCP2 is also known to bind to the
methylated brain-derived neurotrophic factor (BDNF) promoter and is released from it after depolarization, resulting in
unregulated gene expression [31, 32]. BDNF is also a known
activator of the cyclic adenosine monophosphate response
element-binding (CREB) protein, a critical transcription
factor regulating activity-dependent neuronal plasticity.
miR-132 expression is specifically increased by BDNF
through the activation of CREB. Based on these findings, a
regulatory mechanism involving the transcriptional regulation of miR-132 has been proposed for the homeostatic
control of MeCP2 protein during neuronal morphogenesis
[31, 32].
It is also interesting that MeCP2 regulates the expression
of some imprinted genes, and these imprinted genes show
dysregulated expression in Rett syndrome. Moreover, the
induction of miR-184 expression in depolarized cultured
neurons occurs at the same time as the loss of MeCP2
binding upstream of the miR-184 locus. These data suggest
that the regulation of miR-184 expression by MeCP2 is
activity dependent; however, the expression of miR-184 is
not significantly changed in whole brain tissue derived
from MeCP2-deficient mice [33].
DiGeorge Syndrome
DGS is a rare congenital disease that results from
hemizygous deletion of 1.5 to 3 megabases of DNA on
chromosome 22q11.2. DGS arises from de novo deletions
about 90% of the time, with the remaining cases inherited
in an autosomal dominant fashion from a parent who carries
the deletion. DGS is a variable syndrome that commonly
includes a history of recurrent infection, heart defects, and
characteristic facial features. Individuals with DGS have
behavioral and cognitive deficits that lead to childhood
pathologies, including attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and autism spectrum
disorder [34–36]. About 40 genes are deleted in DGS and
are therefore haploinsufficient in patients with DGS.
Interestingly, the Drosha partner, DGCR8, was mapped to
this region [9•]. Heterozygotes of DGCR8 knockout mice
display cognitive delays and reductions in the full complement of pre-miRNAs and mature miRNAs; however, it
remains to be determined whether reduced miRNA levels
are an underlying cause of DGS [37]. Identification of the
downstream targets that are misregulated in these miRNA-
Curr Psychiatry Rep (2010) 12:154–161
deficient mutants would provide further insight into the
pathogenesis of DGS as well as a better understanding of
learning and cognition in general.
Down Syndrome
DS is a chromosomal abnormality in which triplication
of all or part of human chromosome 21 occurs. DS is the
most common genetic cause of cognitive impairment and
congenital heart defects in humans [38–40]. Bioinformatic
analyses have demonstrated that human chromosome 21
harbors five miRNA genes: MiR-99a, Let-7c, MiR-125b-2,
MiR-155, and MiR-802 [41]. Importantly, expression
studies found that these miRNAs are overexpressed in fetal
brain and heart specimens from individuals with DS
compared with those of age- and sex-matched controls.
Based on this, the authors hypothesized that trisomic 21
gene dosage overexpression of human chromosome 21derived miRNAs results in the decreased expression of
specific target proteins and contributes in part to features of
the neuronal and cardiac DS phenotype [41]. A role for
miRNAs in DS is further supported by the finding that
miR-155 downregulates a human gene associated with
hypertension, angiotensin II type-1 receptor (AGTR1) [42].
Indeed, individuals with DS do have lower blood pressure
and lower AGTR1 protein levels than those without DS.
Interestingly, improved computational and experimental
methods now implicate other miRNAs residing on chromosome 21, making them excellent candidates to study for
their role in the molecular pathogenesis of DS.
In summary, miRNAs are abundant in the nervous
system, where they are involved in neural development
and are likely an important mediator of neuronal plasticity.
Because miRNAs play a role in the fine-tuning of protein
production, they could contribute significantly to the
molecular pathogenesis of neurodevelopmental disorders.
Aside from altered miRNA transcription and biogenesis,
the dosage of miRNA genes associated with segmental
duplication could contribute to the phenotypes as well.
Furthermore, the significant numbers of single nucleotide
polymorphisms in the human genome could potentially
create or disrupt the putative miRNA target sites. Therefore,
variations in the target mRNA sequences could also
modulate the activity of specific miRNAs and contribute
to phenotypic variation [43, 44]. It is likely that many of
these variations would affect neuronal miRNAs.
piRNAs and esiRNAs in Neurodevelopmental Disorders
High-throughput sequencing has revealed that there are
many more distinct piRNAs than miRNAs (>50,000 vs
several hundred) [1, 9•]. Most piRNAs map to unique sites
159
in the genome, including intergenic, intronic, and exonic
sequences, and only 17% to 20% of mammalian piRNAs
map to annotated repeats, including transposons and
retrotransposons, suggesting that piRNAs could have
diverse functions [1, 9•]. In Drosophila, Piwi protein was
found to co-localize with Polycomb group proteins to
cluster Polycomb response sequences in the genome and
with Rhino (HP1d), one of five heterochromatin-associated
protein 1-like proteins, to modulate epigenetic silencing
[45–47]. Conversely, Piwi protein and its associated piRNA
can also promote the euchromatic character of certain
heterochromatin regions and their transcriptional activity
[48]. Epigenetic modulations could be the crucial link
between external stimuli and gene expression, in which
the interplay of environmental factors and non-Mendelian
genetics alters gene expression, causing an array of
multisystem disorders, particularly neurodevelopmental
disorders [49, 50]. Given the involvement of piRNAs in
epigenetic modulation, it would be interesting to explore
the potential roles of piRNAs in neurodevelopmental
disorders.
Conclusions
The list of small regulatory RNAs that play a part in the
seamless way the complex nervous system is assembled is
growing steadily. It seems that the roles of small regulatory
RNAs in the physiology and development of the brain are
diverse. They constitute a hidden layer of internal signals
that control various levels of gene expression and epigenetic memory. Understanding the mechanistic function of
these RNAs therefore is crucial to our understanding of
neurodevelopmental disorders.
Acknowledgments The authors would like to thank C. Strauss for
help in editing this manuscript. Dr. Jin is supported by the
International Rett Syndrome Foundation and the National Institutes
of Health. Dr. Jin is also a recipient of the Beckman Young
Investigator Award and the Basil O’Connor Scholar Research Award
and is an Alfred P. Sloan Research Fellow in Neuroscience.
Disclosure No potential conflicts of interest relevant to this article
were reported.
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