Received: 31 January 2017 | Accepted: 5 May 2017

DOI: 10.1002/ajmg.b.32554

REVIEW ARTICLE

A comprehensive review of the genetic and biological

evidence supports a role for MicroRNA-137 in the
etiology of schizophrenia

Kensuke Sakamoto PhD1 | James J. Crowley PhD1,2,3

1 Department of Genetics, University of North

Carolina at Chapel Hill, Chapel Hill, North
Carolina
2 Department of Psychiatry, University of
North Carolina at Chapel Hill, Chapel Hill,
North Carolina
3 Department of Clinical Neuroscience,
Karolinska Institutet, Stockholm, Sweden
Correspondence
Kensuke Sakamoto, PhD, Department of
Genetics, CB#7264, 5097 Genomic Medicine
Building, University of North Carolina at
Chapel Hill, Chapel Hill, NC.
Email: Kensuke_Sakamoto@unc.edu
Funding information
NIH, Grant numbers: R01MH105500,
R01MH110427, R21MH099370,
R21MH102814
Since it was first associated with schizophrenia (SCZ) in a 2011 genome-wide
association study (GWAS), there have been over 100 publications focused on MIR137,
the gene encoding microRNA-137. These studies have examined everything from its
fundamental role in the development of mice, flies, and fish to the intriguing
enrichment of its target gene network in SCZ. Indeed, much of the excitement
surrounding MIR137 is due to the distinct possibility that it could regulate a gene
network involved in SCZ etiology, a disease which we now recognize is highly
polygenic. Here we comprehensively review, to the best of our ability, all published
genetic and biological evidence that could support or refute a role for MIR137 in the
etiology of SCZ. Through a careful consideration of the literature, we conclude that the
data gathered to date continues to strongly support the involvement of MIR137 and its
target gene network in neuropsychiatric traits, including SCZ risk. There remain,
however, more unanswered than answered questions regarding the mechanisms
linking MIR137 genetic variation with behavior. These questions need answers before
we can determine whether there are opportunities for diagnostic or therapeutic
interventions based on MIR137. We conclude with a number of suggestions for future
research on MIR137 that could help to provide answers and hope for a greater
understanding of this devastating disorder.

KEYWORDS
GWAS, microRNA, miR-137, schizophrenia, SNP

1 | G E N E TI C E V I DEN C E F O R MIR137 I N
SC HIZ OPHRENIA
In the largest genome-wide association meta-analysis for SCZ to date
(Schizophrenia Working Group of the Psychiatric Genomics Consortium,
2014) the second most significant association (rs1702294, p = 3.36 × 10−19)
was located in MIR137HG, the host gene encoding miR-137. Figure 1 shows
the pattern of association in the region (chr1: 98,250,000–98,750,000). As
described in greater detail below, multiple reports indicate that genes with
predicted miR-137 target sites are enriched for smaller SCZ GWAS p-values,
raising the possibility that miR-137 regulates a gene network involved in
SCZ. Furthermore, many key predicted miR-137 target genes (e.g., TCF4,
CACNA1C, CSMD1) have been verified molecularly. Throughout this
manuscript, we use the following nomenclature system: MIR137 (human
genomic locus), Mir137 (mouse genomic locus), miR-137 (human and mouse
mature micro RNA); (http://www.genenames.org/cgi-bin/genefamilies/
set/476, http://www.informatics.jax.org/marker/MGI:2676822, http://
www.mirbase.org/help/nomenclature.shtml).
After the first identification of a SCZ risk variant in MIR137
(rs1625579, p = 1.6 × 10−11) (Schizophrenia Psychiatric Genome-Wide
Association Study Consortium, 2011), a number of studies demon-
strated the association between rs1625579 and clinical phenotypes

Am J Med Genet. 2017;9999:1–15. wileyonlinelibrary.com/journal/ajmgb © 2017 Wiley Periodicals, Inc. | 1

2 |
FIGURE 1 Schizophrenia GWAS meta-analysis regional
association plot. A 400 kb region of chromosome 1 is shown,
centered on the most significant SNP, rs1702294 (image from
freeze PGC-SCZ52, https://data.broadinstitute.org/mpg/ricopili).
The x-axis is genomic position, and the y-axis is degree of
association with SCZ (−log10P). Directly genotyped SNPs are plotted
as diamonds, while imputed SNPs are plotted as circles. Color-
coding and symbol size indicate higher linkage disequilibrium (R2)
with rs1702294 (e.g., red points denote an R2 between 0.81 and
1.0, and larger symbol indicates higher R2). Estimated recombination
rates (in cM/Mb) are depicted as a light blue line to demonstrate
the local LD structure. MIR137HG refers to the host gene encoding
miR-137 (also called MIR137). The previously detected lead SNP
(rs1625579) and a potential MIR137 regulatory SNP (rs2660304)
are also indicated and explained in the manuscript.
(e.g., age of onset, psychotic symptoms, and cognitive function)
(Cummings et al., 2013; Kuswanto et al., 2015; Lett et al., 2013), miR-
137 expression in the brain (Guella et al., 2013), brain structure (Cousijn
et al., 2014; Kelly et al., 2014; Kuswanto et al., 2015; Lett et al., 2013; Li
& Su, 2013; Patel et al., 2015; Rose et al., 2014; Wright et al., 2016), and
brain activities (Liu et al., 2014; Mothersill et al., 2014; van Erp et al.,
2014; Whalley et al., 2012). These are summarized in Table 1 and will be
discussed in this manuscript.
The haplotype block harboring MIR137 also contains a second
miRNA gene (MIR2682) which has been reported to have very low
brain expression (Miller et al., 2014), explaining the little attention it
has garnered, and the 5′ portion of the gene DPYD (encoding
dihydropyrimidine dehydrogenase), which itself has an independent
genome-wide significant association with SCZ in its 3′ region (Ripke,
2013; Schizophrenia Working Group of the Psychiatric Genomics
Consortium, 2014). Copy number variants (CNVs) in the region shown
in Figure 1 are very rare, but have proven informative. In particular,
hemizygous deletions in this region of chr1p21.3 encompassing both
DPYD and MIR137 have been described in ∼10 cases and are
associated with a syndrome consisting primarily of intellectual
disability, autism-spectrum disorder (ASD), and obesity (Carter et al.,
2011; D’Angelo, Moller Dos Santos, Alonso, & Koiffmann, 2015;
Willemsen et al., 2011). Some investigators initially proposed DPYD to
be the major gene contributing to this syndrome (Carter et al., 2011;
D’Angelo et al., 2015), which seemed sensible since DPYD deficiency
(OMIM #274270; DPYD encodes for the rate-limiting enzyme in the
catabolism of the pyrimidine bases), an autosomal recessive disease, is
SAKAMOTO AND CROWLEY
characterized by childhood onset neurological problems, including
developmental delay. Critically, however, two recent reports from
Pinto et al. (2014) and Tucci, Ciaccio, Scuvera, Esposito, and Milani
(2016) have identified children whose deletions in this region overlaps
only MIR137, leaving DPYD unaffected. They both show that
hemizygous loss of MIR137 alone is sufficient to produce all three
features of this syndrome (intellectual disability, ASD, and obesity).
While these CNV data may seem to suggest that MIR137 is more
relevant to ASD than SCZ, it is important to note that these case reports
describe children who have yet to enter the risk period for SCZ and, of
course, a one-copy deletion may lead to a more profound phenotype
than common SNPs, which likely have a more subtle effect on function.
In support of this idea, the Cross-Disorder Group of the Psychiatric
Genomics Consortium (PGC) reported that, in an analysis of five major
psychiatric disorders, a best-fit model predicted common variants in
MIR137 to jointly influence risk to SCZ and ASD, but not attention deficit
hyperactivity disorder (ADHD), bipolar disorder, or major depression
(Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013).
2 | E S S E N T I A L B A C K G R O U N D ON
microRNAs
MicroRNAs (miRNAs) are small non-coding RNA species of ∼22
nucleotides which negatively regulate mRNA stability or translation,
and in turn, alter various cellular functions (Bartel, 2004; Lagos-
Quintana, Rauhut, Lendeckel, & Tuschl, 2001; Wright, Turner, Calhoun,
& Perrone-Bizzozero, 2013). Importantly, a single miRNA can regulate
the expression of many target genes, and, as such, miRNAs often act as
key signaling nodes regulating complex biological networks.
The canonical miRNA biogenesis process is nicely summarized in
previous articles (Bartel, 2004; Kim & Kim, 2007; Lagos-Quintana et al.,
2001; Wright et al., 2013). In short, miRNAs are transcribed from
intergenic non-coding RNA (such is the case for miR-137) or introns of
protein coding genes (introgenic microRNA) (Kim, Han, & Siomi, 2009;
Liu et al., 2008). The single-stranded “primary” miRNA forms a stem-
loop structure and is then cleaved in the nucleus into a ∼70 nucleotide
“precursor” miRNAs by a complex composed of Drosha and DGCR8
(Denli, Tops, Plasterk, Ketting, & Hannon, 2004; Gregory et al., 2004;
Han et al., 2006). Following export to the cytoplasm, the precursor
miRNA is further processed by Dicer into its final ∼22 nucleotide form
(Chendrimada et al., 2005; Forstemann et al., 2005). Finally, miRNAs
are loaded onto the RNA-induced silencing complex (RISC) where they
bind to their target RNAs, induce mRNA degradation and/or reduce
translation efficiency (Wightman, Ha, & Ruvkun, 1993; Wu & Belasco,
2008; Zeng, Yi, & Cullen, 2003).
3 | m i R N A s A R E E S S E N T I A L FO R P R O PE R
BRA IN D EVELOPMENT AND FUNCTION
A series of studies over the past decade have revealed that finely-tuned
miRNA function across the lifespan is critical for orchestrating cell
proliferation, differentiation, migration, and death in the brain (Cheng,
SAKAMOTO AND CROWLEY | 3

TABLE 1 Putatively functional schizophrenia-associated variants in the MIR137 locus

Variant
(SNP ID) Study type Effects of the risk alleles References
−11
rs1625579 GWAS  Association with SCZ, 9,394 cases and 12,462 controls, p = 1.6 × 10 Schizophrenia Psychiatric
Genome-Wide Association
Study Consortium (2011)
Clinical  Earlier disease onset Lett et al. (2013)
symptoms  More severe positive symptoms and cognitive function Cummings et al. (2013)
 More severe negative symptoms, poorer attention and processing speed Kuswanto et al. (2015)
miR-137  Decreased miR-137 expression in the DLPFC Guella et al. (2013)
expression
Brain  Decreased fronto-striatal brain white matter integrity Kuswanto et al. (2015)
structure  Decreases in occipital, parietal and temporal lobe gray matter concentration Wright et al. (2016)
 Reduced white matter integrity, smaller hippocampus, larger lateral ventricles Lett et al. (2013)
Brain  Higher left DLPFC activation van Erp et al. (2014)
function  Higher functional connectivity between DLPFC and left hippocampi than heterozy- Liu et al. (2014)
gous individuals
 Increased functional connectivity between right amygdala and frontal regions Mothersill et al. (2014)
 Higher activity in the posterior right medial frontal gyrus, BA6 Whalley et al. (2012)
rs1702294 GWAS  Association with SCZ, 36,989 cases and 113,075 controls, p = 3.36 × 10−19 Schizophrenia Working
Group of the Psychiatric
Genomics Consortium
(2014)
rs2660304 GWAS  Association with SCZ (in LD with a reported SCZ-associated SNP, rs1198588 Duan et al. (2014)
(R2 = 0.74, based on the 1000 Genomes project))
 Association with SCZ in an Ashkenazi Jewish population Goes et al. (2015)
miR-137  Decreased promoter activity Warburton et al. (2016)
expression  Lower level of endogenous miR-137 expression Siegert et al. (2015)

Other Effects of the variation References

variant
VNTR miR-137  pre-miR-137 carrying 9 and 13 repeats leads to reduced miR-137 expression Mamdani et al. (2013)
expression  VNTR length affects the secondary structure of pre-miR-137 stem-loop and impacts Bemis et al. (2008); Strazisar
expression of mature miR-137 et al. (2015)

GWAS, genome-wide association study; SCZ, schizophrenia; DLPFC, dorsolateral prefrontal cortex; BA6, Brodmann area 6; LD, linkage disequilibrium;
VNTR, variable number tandem repeat.

Pastrana, Tavazoie, & Doetsch, 2009; Friedman et al., 2009; Hebert &
De Strooper, 2007; Shibata, Nakao, Kiyonari, Abe, & Aizawa, 2011). At
the developmental level, conditional deletion of Dicer, an essential
component of miRNA genesis, in the CNS results in abnormal neuronal
differentiation and brain structure (Kawase-Koga, Otaegi, & Sun, 2009;
Saurat, Andersson, Vasistha, Molnar, & Livesey, 2013). In mature brain,
miRNAs also act to modulate morphology and function. For instance,
miR-132 and miR-212 demonstrate expression that is tightly regulated
by neuronal activity. These miRNAs have the ability to modulate a
number of neuronal and behavioral phenotypes, including synapse
number, synaptic efficiency, dendrite complexity, and context depen-
dent short-term memory (Cheng et al., 2007; Edbauer et al., 2010;
Hansen, Sakamoto, Wayman, Impey, & Obrietan, 2010; Impey et al.,
2010; Remenyi et al., 2010; Wayman et al., 2008). Beyond neurons,
miRNAs control the differentiation and maintenance of glial cells in both
the developing and mature brain (Hong, Jiang, & Li, 2014; Howng,
Huang, Ptacek, & Fu, 2015; Kawase-Koga et al., 2009; Zhang et al.,
2015).
Dysregulation of miRNAs has been associated with several
neurological and neuropsychiatric disorders (Beveridge et al., 2008; Klein
et al., 2007; Kim et al., 2007; Packer, Xing, Harper, Jones, & Davidson,
2008; Shioya et al., 2010; Wang et al., 2008; Xu, Hsu, Karayiorgou, &
Gogos, 2012; Xu, Li, Wang, & Gao, 2008; Zhou et al., 2009). Of note,
chromosome 22q11.2, a locus strongly connected to neurocognitive
deficits with a high risk of SCZ, contains the miRNA microprocessor
component gene, DGCR8. Multiple miRNAs are dysregulated in the blood
of individuals with 22q11.2 deletion syndrome (22q11DS), and there is a
significant inverse correlation between miRNA expression and hippo-
campal and whole brain volume in 22q11DS cases (Merico et al., 2014;
Sellier et al., 2014; Stark et al., 2008; Zhao et al., 2015).
4 | MicroRNA -137
miR-137 was first identified in mice during tissue-specific small RNA
profiling and was also shown to be highly conserved and expressed
4 |
across mammalian and non-mammalian vertebrates (Lagos-Quintana
et al., 2002). Human MIR137 is located within host gene MIR137HG
(chr1:98,453,556–98,515,249). The 86bp hairpin sequence within
pre-miR-137 is highly conserved from humans to zebrafish, represent-
ing ∼450 million years since the last common ancestor (Kumar &
Hedges, 1998). This illustrates that miR-137 has assumed a critical role
in mammalian biology. In addition to the pre-miRNA sequence, there is
also high evolutionary conservation of several key regulatory elements
surrounding MIR137 (e.g., transcription factor binding sites, epigenetic
marks, etc.), suggesting that some regulatory mechanisms may also be
conserved. Figure 2 provides an overview of several of these features,
many of which will be referred to in the discussion below.
5 | m i R - 1 3 7 T A R G E T G E N E S AN D
SC HIZ OPHRENIA G ENOM ICS
Bioinformatic methods cannot perfectly predict genes targeted by
miRNAs, due to imperfect base-pairing between miRNAs and their
targets. Therefore, investigators have taken multiple informatics and
experimental approaches to generate meaningful lists of miR-137 target
genes for pathway analysis. These include: 1) algorithm-based comple-
mentary base pairing analysis (e.g., Target Scan, Miranda, miRdb, etc.)
FIGURE 2 Regulatory DNA surrounding MIR137. A number
of key tracks from the UCSC Genome Browser (hg19 assembly)
are shown. These include common SNPs (MAF > 0.05), with red
arrows pointing to the lead SNP (rs1702294), previously
detected lead SNP (rs1625579), and a potential MIR137
regulatory SNP (rs2660304). “VNTR” depicts the position of a
putatively functional variable number tandem repeat (VNTR).
The bindings sites for RE1-Silencing Transcription factor (REST)
from two cell lines (ENCODE ChIP-seq data) are also shown. The
“Txn Factor ChIP” track summarizes transcription factor ChIP-
seq data for 161 factors and the “DNase Clusters” track
summarizes DNaseI hypersensitivity clusters in 125 cell types.
“CpG Islands” shows regions with high CpG sequence frequency,
while “Hypomethylation” shows regions with depleted DNA
methylation in human neuronal progenitor cells. “H3K4me3”
shows histone H3 Lysine 4 trimethylation (H3K4me3) sites, a
marker associated with active transcription start sites, detected
in postmortem human frontal cortex grey matter. “100 Vert.
Cons” shows base-level conservation (PhyloP score) for 100
different vertebrate species. The red rectangles point to
potential key transcription regulatory regions.
SAKAMOTO AND CROWLEY
(Agarwal, Bell, Nam, & Bartel, 2015; Betel, Wilson, Gabow, Marks, &
Sander, 2008; Wong & Wang, 2015), 2) gene expression analysis after
immunoprecipitating the RISC complex or after altering miR-137
expression (Boudreau et al., 2014; Collins et al., 2014; Hill et al., 2014;
Tamim et al., 2014), and 3) reporter gene activity or quantitative protein
measures (e.g., luciferase assay, proteomics, Western blotting) (Chen,
Wang et al., 2011; Kim et al., 2012; Kwon, Wang, & Tsai, 2013; Siegert
et al., 2015). Given the strengths and weaknesses of these various
approaches, most investigators have chosen to integrate data from two
or more of these methods in generating miR-137 target gene lists.
Bioinformatic algorithms predict miR-137 targets by calculating
the likelihood of base-pairing with target mRNA untranslated regions
(UTRs). The available algorithms vary in the weight given to different
criteria for this calculation, and so their results vary. For example,
TargetScan searches primarily for a complementary match between
the 3′ UTR of an mRNA and the miRNA “seed” sequence, which is the
term given to the 5′ 2–8 nucleotides critical for target detection
(Agarwal et al., 2015; Lewis, Burge, & Bartel, 2005). In its latest version
(release 7.1, June 2016), TargetScan predicts N = 1,305 transcripts
with phylogenetically conserved miR-137 binding sites.
Computationally predicted miR-137 targets have been repeatedly
associated with SCZ. For example, genes with TargetScan-predicted
miR-137 target sites are enriched for smaller GWAS p-values, raising
the possibility that miR-137 regulates a gene network involved in SCZ
(Schizophrenia Psychiatric Genome-Wide Association Study Consor-
tium, 2011). Wright et al. (2015) further categorized miR-137 targets
by pathway-specific gene sets, performed a similar analysis, and found
that potential miR-137 targets are particularly enriched in SCZ risk
genes involved in axonal guidance signaling, Ephrin receptor signaling,
long-term potentiation, PKA signaling, and Sertoli cell junction
signaling. Additional evidence comes from a recent rare variant study
by Genovese et al. (2016), who collated disruptive ultra-rare variants
(dURVs) in exome sequencing data from Swedish SCZ cases and
controls. In addition to observing an overall burden of dURVs in cases,
they reported a significant enrichment within predicted miR-137
targets (Genovese et al., 2016). Finally, taking an imaging genetics
approach, Potkin et al. (2010) showed that miR-137 targets are
enriched for smaller GWAS p-values in a study of dorsolateral
prefrontal cortex (DLPFC) activation during a working memory task.
Experimentally derived miR-137 targets, from a variety of genomic
approaches, have also been associated with schizophrenia. It is
important to note that these studies, summarized below, employed a
wide range of tissues, cell lines, expression platforms, and miR-137
manipulation methods. As a result, the overlap in miR-137 targets is
limited, suggesting that miR-137 targets vary with tissue, cell type, and
proliferative status (Boudreau et al., 2014; Collins et al., 2014; Hill et al.,
2014; Tamim et al., 2014). First, Collins et al. (2014) overexpressed miR-
137 in the human neuroprogenitor cell line RenCell-VM and used RNA
sequencing to nominate down-regulated genes as miR-137 targets.
They noted that several SCZ-related pathways were up-regulated 48 hr
after miR-137 overexpression, including: calcium channels, synaptic
proteins, FMRP-interacting RNAs, and genes forming the major
histocompatibility complex (MHC). Second, Hill et al. (2014) took a
SAKAMOTO AND CROWLEY
similar approach in the human neural progenitor cell line CTXOE03,
finding that genes down-regulated after miR-137 over-expression were
enriched for involvement in neuronal differentiation and included
genome-wide significant risk loci for SCZ (e.g., MAD1L1 and DPYD).
Interestingly, a recent study demonstrated that an increased polygenic
risk score within the miR-137 targets that Hill et al. (2014) detected was
associated with significantly lower performance on intelligence
quotient, working memory and episodic memory (Cosgrove et al.,
2017). Functional brain imaging during a memory task further revealed
that it is also associated with increased activation of the right inferior
occipital gyrus (Cosgrove et al., 2017). Third, Boudreau et al. (2014) used
immunoprecipitation of the RISC complex from human brain motor
cortex and cingulate gyrus to directly pull out mRNAs being actively
targeted by miRNAs (HITS-CLIP). Expression analysis revealed 88
transcripts with miR-137 binding sites (TargetScan seeds), 24 of which
overlapped with genes from a SCZ meta-analysis (SzGene database
(Allen et al., 2008)) or genes associated with prefrontal cortex
abnormalities in psychiatric patients (Allen et al., 2008; Kim & Webster,
2010). Of note, 5 SCZ GWAS associated genes including TCF4, a
previously established miR-137 target (Kwon et al., 2013), were
included in this list (Boudreau et al., 2014). Fourth, some groups have
taken a proteomic approach to detect translationally regulated miR-137
targets (Hao et al., 2015; Ren et al., 2015; Schouten et al., 2015), though
their relevance to SCZ is as yet unclear.
Highly reliable miR-137 targets empirically demonstrated by
molecular biological methods have been well summarized in previous
reviews (Mahmoudi & Cairns, 2017; Wright et al., 2013). Among these
validated targets are genes unquestionably associated with SCZ, such as
TCF4, CACNA1C, CSMD1, and C10orf26 (Kwon et al., 2013; Schizophre-
nia Psychiatric Genome-Wide Association Study Consortium, 2011).
Furthermore, recent validated miR-137 targets include additional
synaptic genes, such as those encoding Synaptophysin and glutamate
receptor subunit GluA1 (Olde Loohuis et al., 2015; Siegert et al., 2015).
The results summarized here suggest that a more precise analysis of
miR-137 regulated gene networks in a variety of tissues, cell types, and
developmental stages would be valuable as we try to understand the role
of miR-137 in SCZ etiology. For example, recent improvements in single-
cell based gene expression analysis may contribute to a more precise
description of the miR-137 gene network (Zeisel et al., 2015) that could be
used to refine the role of this pathway in neuropsychiatric disorders.
6 | W H E R E AN D W HE N I S m i R - 1 3 7
EXPRESSED?
An examination of MIR137HG expression across >50 adult human tissues
from GTEx (http://www.gtexportal.org) reveals highly enriched brain
expression, with the highest expression in frontal cortex (Brodmann area
9, BA9) and this is supported by multiple publications (Consortium, 2015;
Guo et al., 2014; Landgraf et al., 2007; Ludwig et al., 2016). Nearly all
tissues, however, show measurable expression of miR-137 in GTEx and
there is a growing appreciation of the role miR-137 plays in the cell cycle
and tumor formation in non-brain tissues (see below).
| 5
Regarding when miR-137 is expressed, it is becoming clear that it
appears very early in development and is necessary for life. Crowley et al.
(2015) showed that mice lacking expression of Mir137 (homozygous
constitutive knockout) resulted in embryonic lethality before develop-
mental day 11.5. Others have shown that miR-137 is expressed in mouse
embryonic stem (ES) cells and regulates proper cell differentiation through
specific target gene regulation (Jiang, Ren, & Nair, 2013; Tarantino et al.,
2010). According to Tarantino et al. (2010), a loss of miR-137 expression
during ES cell differentiation resulted in impaired neuronal gene
expression and morphogenesis. Hollins et al. (2014) demonstrated that
miR-137 expression is consistently high in the rat forebrain and midbrain
at the late developmental stage (E12-P0). Consistent with this theme,
other work has revealed a crucial role for miR-137 in adult neurogenesis
and neuronal maturation (Smrt et al., 2010; Sun et al., 2011). Furthermore,
the BrainSpan consortium performed small RNA-sequencing of human
brain and demonstrated high miR-137 expression across development in
several brain regions (Miller et al., 2014).
miR-137 expression is not limited to neurons. More work is
needed to determine cell-type specificity, but the literature shows that
miR-137 is not only present in glial cells, but highly involved in glial cell
function and cell-cycle control, as demonstrated by repeated
association of decreased miR-137 expression in glioblastoma (Chen
et al., 2012; Koshkin, Chistyakov, Nikitin, Konovalov, Potapov,
Usachyov et al., 2014; Koshkin, Chistyakov, Nikitin, Konovalov,
Potapov, Usachev et al., 2014; Silber et al., 2008; Visani et al., 2014).
7 | S T E M C E L L P R O L I F E R A T I O N AN D
DI FFERENTI ATI ON
SCZ is considered by some to be a neurodevelopmental disorder (Kinros,
Reichenberg, & Frangou, 2010; Rapoport, Giedd, & Gogtay, 2012;
Stachowiak et al., 2013), thus miR-137’s role in neurodevelopment may
be of etiological importance. The literature suggests that miR-137
controls proliferation and differentiation in both the developing and
mature brain, but its direction of effect is context-dependent. During
development, miR-137 is highly enriched in mitotic phase ES cells and
controls differentiation by targeting transcription regulators (e.g., KLF4,
TBX3, LSD1), and loss of miR-137 expression results in abnormal
neuronal morphology (Jiang et al., 2013). Consistent with Jiang et al.
(2013), Sun et al. (2011) demonstrated that miR-137 overexpression
decreases proliferation of mouse embryonic neural stem cells and
results in premature neuronal differentiation. Moreover, Tarantino et al.
(2010) demonstrated that miR-137 increases differentiation of mouse
embryonic stem cells and suppression of miR-137 blocked the
differentiation induced by leukemia inhibitory factor (LIF) withdrawal.
These reports demonstrate the pro-differentiation feature of miR-137
in embryonic neuronal stem cells.
In contrast to its effect on embryonic neurogenesis, Smrt et al. (2010)
reported that miR-137 overexpression negatively controls adult neuronal
stem cell differentiation. They confirmed that miR-137 targets are
enriched in the neuronal lineage (compared to the astrocytic lineage) and
that miR-137 is highly expressed in the adult dentate gyrus of the
6 |
hippocampal formation, an area highly active in adult neurogenesis. Smrt
et al. (2010) also reported that miR-137 overexpressed cells had an 80%
decrease in the proportion of matured neurons. Other researchers have
demonstrated that miR-137 overexpression enhances proliferation and
inhibits differentiation of adult neuronal stem cells (Szulwach et al., 2010).
However, consistent with the effect on the developing brain, Santos et al.
(2016) showed that miR-137 is expressed much more highly in the non-
germinal striatum than in the subventricular zone (SVZ, an area of adult
neurogenesis) in 2-month-old mice and that miR-137 is upregulated
during lineage progression and the differentiation of neural stem cells.
They further showed that overexpression of miR-137 in isolated neural
stem cell cultures from 2-month-old mouse SVZ increases neuronal
differentiation and decreases cell proliferation (Santos et al., 2016). These
results suggest that miR-137 has a context-dependent role and function
during neuronal stem cell development. Given the diversity of predicted
miR-137 targets in different cell types (Boudreau et al., 2014; Collins et al.,
2014; Hill et al., 2014; Tamim et al., 2014), it is not surprising that the miR-
137 regulated gene network is dependent on cell lineage context. A
simple, yet important, methodological difference in these experiments
included the magnitude of miR-137 overexpression, which may affect
outcome. Again, we note that the use of a precise gene network analysis in
individual cells could help to address these questions.
8 | NEURONA L MATURA TION AND
S YN A P TI C FU N CT IO N
A reduction of synaptic form and function are cellular features
frequently observed in psychiatric disorders, including SCZ and autism
(Garey et al., 1998; Glantz & Lewis, 2000; Glausier & Lewis, 2013).
Recent publications identify miR-137 as an important regulator of
neuronal maturation and synaptic function in the adult brain. Several
researchers have indicated that miR-137 targets include synaptic
genes (Collins et al., 2014; Siegert et al., 2015; Strazisar et al., 2015).
Willemsen et al. (2011) reported finding enriched expression of pre-
miR-137 in synaptosomes. Moreover, Smrt et al. (2010) showed that
overexpression of miR-137 decreases dendritic complexity, spine
density, and maturation of newborn neurons in adult hippocampus.
Investigators have recently examined the precise role of miR-137
in synaptic regulation. Siegert et al. (2015) demonstrated, by electron
microscopy, that overexpression of miR-137 in the adult mouse
hippocampus alters synaptic vesicle distribution; with miR-137
overexpression, synaptic vesicles distributed more distantly from
the release site, while the overall number of vesicles was not affected.
This result was further supported by their finding that when sustained
low-frequency electrostimulation was applied to dentate granule cells,
the amplitude of synaptic responses evoked at the mossy fiber-CA3
synapse reached a lower plateau in miR-137 overexpressed slices.
Siegert et al. (2015) also showed that this phenotype is mediated by the
regulation of a miR-137 target synaptotagmin-1 (Syt1), suggesting that
miR-137 negatively regulates presynaptic neurotransmitter release.
Verma, Augustine, Ammar, Tashiro, and Cohen (2015) confirmed the
presynaptic role of miR-137 by demonstrating that Drosophila
SAKAMOTO AND CROWLEY
melanogaster miR-1000 (a potential ortholog of mammalian
miR-137) represses the vesicular glutamate transporter (VGlut) and
negatively regulates glutamate release at the synapse.
Other researchers have documented a postsynaptic role for
miR-137. Olde Loohuis et al. (2015) showed that miR-137 increases
silent synapses by repressing AMPA receptor-mediated synaptic
transmission through down-regulation of AMPA receptor subunit
GluA1. They also found that miR-137 is transiently upregulated in
response to metabotropic glutamate receptor 5 (mGluR5) and miR-137
is crucial for mGluR-mediated long-term depression (LTD). These
results suggest that miR-137 controls synaptic efficacy and mGluR-
dependent synaptic plasticity and may contribute to glutamatergic
dysfunction in SCZ (de Bartolomeis, Buonaguro, & Iasevoli, 2013;
Moghaddam & Javitt, 2012). This result suggests that miR-137 is also
involved in the regulation of dendritically localized mRNAs, which is a
critical process for mGluR-LTD (Huber, Kayser, & Bear, 2000; Klann &
Dever, 2004; Snyder et al., 2001).
9 | FU N CTION IN GLIA
Several groups have documented the involvement of miR-137 in the
biology of diverse cancers (e.g., brain, oral, colorectal, lung, gastric,
squamous cell carcinoma, breast, bladder, melanoma) (Balaguer et al.,
2010; Bandres et al., 2009; Bennett, Bemis, Norris, & Shellman, 2013;
Chen, Chen et al., 2011; Chen, Wang et al., 2011; Dacic, Kelly, Shuai, &
Nikiforova, 2010; Huang et al., 2009; Kozaki, Imoto, Mogi, Omura, &
Inazawa, 2008; Langevin et al., 2011; Liu et al., 2011; Shimizu et al.,
2013; Tezcan et al., 2014; Zhao et al., 2012; Zhu et al., 2013). In
general, miR-137 has been identified as a tumor suppressor. Reduced
miR-137 expression is observed in glioblastoma cells, and higher grade
glioblastoma shows greater reduction (Chen et al., 2012; Koshkin,
Chistyakov, Nikitin, Konovalov, Potapov, Usachyov et al., 2014;
Koshkin, Chistyakov, Nikitin, Konovalov, Potapov, Usachev et al.,
2014; Silber et al., 2008; Visani et al., 2014). In fact, miR-137
expression in blood cells has been suggested as a biomarker for human
glioblastoma (Li, Li, Li, Shi, & Chen, 2016).
The effect of glial miR-137 on cognitive function, however, is
poorly understood. Given the critical roles of glial cells in neuro-
cognitive functions (Cotter, Pariante, & Everall, 2001; Dzyubenko,
Gottschling, & Faissner, 2016; Jo, Law, & Chung, 2014; Stogsdill &
Eroglu, 2016) and SCZ pathology (Bernstein, Steiner, Guest,
Dobrowolny, & Bogerts, 2015) and the fact that some miR-137 target
genes are expressed in glial cells (Tamim et al., 2014), it would not be
surprising if miR-137 mediated glial regulation has a critical role in fine-
tuning brain function. For example, deficits in myelin, reduced
oligodendrocytes, and altered expression of myelin/oligodendrocyte
-related genes are found in SCZ, which could explain white matter
abnormalities in SCZ (Goudriaan et al., 2014; Hof, Haroutunian,
Copland, Davis, & Buxbaum, 2002; Kerns et al., 2010; Regenold et al.,
2007; Schmitt et al., 2009; Uranova, Vikhreva, Rachmanova, &
Orlovskaya, 2011). Also, dysfunctional astrocytes, which have key
roles in the synaptic metabolism of neurotransmitters (e.g., glutamate,
SAKAMOTO AND CROWLEY
GABA, monoamines, and purines), may contribute to disturbed
neurotransmission in SCZ (Bernstein et al., 2015; Sofroniew & Vinters,
2010). In addition, microRNAs have been proven to have critical roles
in glial cell development and function (Bian, Xu, & Sun, 2013;
Karthikeyan, Patnala, Jadhav, Eng-Ang, & Dheen, 2016; Zheng, Li,
Huang, & Qiu, 2012). For example, miR-124 in microglia is down-
regulated during autoimmune inflammation of the CNS, and reduction
of miR-124 in microglia activates these cells. (Ponomarev, Veremeyko,
Barteneva, Krichevsky, & Weiner, 2011). Interestingly, glial miR-137
shares a large number of putative targets with miR-124 (Schouten
et al., 2015; Silber et al., 2008; Tamim et al., 2014). In sum, although
current knowledge of miR-137’s role in glial cells is limited, these
studies suggest potential functions of miR-137 in the fine tuning of
brain function through glial cell regulation.
10 | A NI M A L M O D E L S O F m i R - 1 3 7
D Y S F U N C T IO N
Mouse, fly, and fish all have models of miR-137 manipulation available
for study. Crowley et al. (2015) reported that mice with a whole body
knockout of Mir137 are embryonically lethal between embryonic days
4.5 and 11.5. Interestingly, heterozygous knockouts showed no
striking behavioral phenotype, likely due to compensated miR-137
expression (Crowley et al., 2015). Siegert et al. (2015) showed that
virus-mediated miR-137 overexpression in the dentate gyrus impaired
induction of mossy fiber long-term potentiation and induced a deficit
in hippocampal-dependent learning and memory. In flies, knockout of
Drosophila miR-1000 (ortholog of mammalian miR-137) led to an early-
onset movement disorder and higher apoptosis in the brain, as
detected by Caspase-3 activity (Verma et al., 2015). In fish,
developmental suppression of miR-137 in zebrafish impaired both
embryonic and larval touch-sensitivity without compromising overall
anatomical development (Giacomotto et al., 2016).
Given the severe phenotypes associated with loss of miR-137 in
multiple species (particularly embryonic lethality in mice), there is a need
for a conditional knockout of Mir137 in mice and other species. It will be
important to examine the effects of miR-137 dysfunction at different
developmental time-points, tissues, and cell types. Furthermore, only a
few behavioral domains have been examined thus far (e.g., memory,
anxiety, sensorimotor gating), but methods for other more sophisticated
measures of various endophenotypes are improving (Achim et al., 2011;
Hart et al., 2014; Nestler & Hyman, 2010; van Scheltinga et al., 2013;
Winton-Brown, Fusar-Poli, Ungless, & Howes, 2014).
11 | W H A T M O L E C U L A R ME C H A N I S M ( S )
U ND E R L I E T HE M I R 1 3 7 S CH I ZOP H R E NI A
ASSOCIATION?
Common-variant GWAS associations for complex traits (like SCZ) are
usually not explained by protein-coding variants but, on the other hand,
they are often highly enriched for regulatory DNA (Hindorff et al., 2009).
| 7
Large-scale resources such as ENCODE (Consortium, 2012) have
produced catalogs of putative regulatory DNA sequences, such as those
with open chromatin, acetylated histones, enhancer function, or
methylated DNA, to name but a few (see Figure 2). In other disorders,
there are documented examples of causal regulatory SNPs explaining
GWAS signals (Fogarty, Cannon, Vadlamudi, Gaulton, & Mohlke, 2014;
Nicolae et al., 2010; Smemo et al., 2014). This has generated great
interest in identifying variants in the MIR137 locus that may help explain
the GWAS signal via altered expression, post-transcriptional processing
or function of miR-137 (Consortium, 2015; Fromer et al., 2016;
Gianfrancesco et al., 2016; Ward & Kellis, 2012; Yang, Li, Jiang, Zhou, &
Qu, 2013). Gianfrancesco et al. (2016) defined seven potential
regulatory regions upstream of MIR137 using a phylogenetic approach
to define evolutionarily conserved regions (ECRs). Three out of these
seven ECRs overlapped ENCODE-defined chromatin signatures in the
brain. They further showed that four ECRs have genome-wide
significant SCZ GWAS SNPs in or adjacent to their sequence.
Warburton, Breen, Bubb, and Quinn (2016) demonstrated that
rs2660304 (a SNP located ∼400 bp upstream of pre-miR-137) is in high
LD with the top SCZ-associated SNP rs1625579 (R2 = 0.96), and that the
major allele (the SCZ risk allele) of rs2660304 decreases promoter
activity. This result is consistent with Siegert et al. (2015) recent work
documenting a lower level of endogenous miR-137 expression in human
fibroblast-derived neurons with the major (risk) allele of rs2660304. Of
note, rs2660304 has also been associated with SCZ in an Ashkenazi
Jewish population (Duan et al., 2014; Goes et al., 2015). It is important to
state that, as of this writing, no genome-wide expression QTL (eQTL)
study has associated rs2660304 with expression of MIR137, but few
eQTL studies have closely examine microRNAs or their host genes and
most brain eQTL studies at this point are underpowered. In sum, the
existing in vitro molecular evidence appear consistent with at least one
SCZ risk variant (rs2660304) being associated with reduced activity of
the MIR137 promoter. Furthermore, another SCZ risk allele in this
region, rs1625579, is associated with decreased miR-137 expression in
the dorsolateral prefrontal cortex (DLPFC) (Guella et al., 2013),
providing convergent evidence.
Another putatively functional DNA variant found just upstream of
MIR137 consists of a variable number tandem repeat (VNTR, see
Figure 2). By overexpressing pre-miR-137 with various numbers of
repeats (3–13) in HEK293 cells, Mamdani et al. (2013) demonstrated
that pre-miR-137 carrying 9 and 13 repeats leads to significantly
reduced miR-137 expression. Two additional studies provide evidence
that VNTR length affects the secondary structure of pre-miR-137
stem-loop and impacts expression of mature miR-137 (Bemis et al.,
2008; Strazisar et al., 2015). While these findings suggest that VNTR
repeat number potentially affects levels of miR-137, it is important to
note that there is currently insufficient genetic evidence associating
VNTR repeat length with SCZ, possibly due to the low allele frequency
of the higher VNTR repeat, which reduces statistical power (Duan
et al., 2014; Egawa et al., 2013; Strazisar et al., 2015; Warburton,
Breen, Rujescu, Bubb, & Quinn, 2015). MIR137 has been identified as a
target gene of Repressor Element-1 Silencing Transcription Factor
(REST) (Soldati et al., 2013; Warburton et al., 2015), a key
8 |
transcriptional regulator of neuron-specific genes (Ballas & Mandel,
2005; Ooi & Wood, 2007; Roopra, Huang, & Dingledine, 2001; Singh,
Kagalwala, Parker-Thornburg, Adams, & Majumder, 2008; Tamminga
& Zukin, 2015). Soldati et al. (2013) showed that miR-137 expression is
low in Huntington’s disease model cells and that its expression
increases after REST knockdown. Warburton et al. (2015) confirmed
binding of REST to the miR-137 promoter by chromatin immunopre-
cipitation (ChIP). Given the potential involvement of REST in SCZ
pathology, REST-mediated miR-137 regulation could be an important
molecular mechanism (Tamminga & Zukin, 2015).
Epigenetic mechanisms constitute another source of transcrip-
tional regulation. miR-137 transcription is regulated by three
hypomethylation sites (see Figure 2) (Kozaki et al., 2008; Song et al.,
2013). Several cancer cell studies have reported miR-137 expression
modulation during altered DNA methylation (Chen, Wang et al., 2011;
Silber et al., 2008; Zhu et al., 2013). In mouse adult neuronal stem cells,
miR-137 is regulated by the DNA methyl-CpG-binding protein MeCP2
and transcription factor Sox2 (Szulwach et al., 2010), supporting the
importance of DNA methylation in miR-137 regulation. Downstream,
miR-137 itself controls the expression of multiple epigenetic modula-
tor genes. For example, miR-137 regulates Ezh2, a histone (H3K27)
methyltransferase in neuronal stem cells (Szulwach et al., 2010). Sun
et al. (2011) demonstrated that miR-137 targets the histone lysine-
specific demethylase 1 (LSD1), a transcriptional co-repressor of
nuclear receptor TLX. TLX, a regulator of neural stem cell self-renewal,
induces feedback loop repression of miR-137 transcription by
recruiting LSD1 to the miR-137 promoter (Jiang et al., 2013).
Moreover, histone H3K4 demethylase Jarid1b (also known as
KDM5b), which suppresses transcription through demethylation of
transcription start sites, is also targeted by miR-137 during neuronal
differentiation of mouse ES cells (Tarantino et al., 2010). Together,
these results suggest that epigenetic chromatin modulation is involved
in a miR-137 self-regulation feedback loop.
In sum, a growing body of molecular studies are beginning to
reveal functional DNA variants regulating MIR137 that may explain
associations with SCZ. Other investigators are exploring the down-
stream gene network regulated by miR-137, including self-feedback.
Furthermore, recent studies have isolated physiological stimulators of
MIR137, including metabotropic glutamate receptor stimulation,
seizure activity, and propofal (Fan, Zhou, Qin, & Tao, 2016; Olde
Loohuis et al., 2015; Schouten et al., 2015). Without question, given
the diverse activities of this microRNA, further molecular work is
needed to fully understand what regulates miR-137, and what it
regulates, that may be relevant to the etiology of SCZ.
12 | D O E S MIR137 V A R I A T I O N I N F L U E N C E
HUMA N B RAIN STRUCTUR E A ND
FU N CTIO N?
Structural brain imaging studies have consistently identified changes in
SCZ (e.g., altered volume of white matter, hippocampus, amygdala, etc.),
and therefore, linking them with recent genetic findings is a major research
SAKAMOTO AND CROWLEY
focus (Baare et al., 2001; Samartzis, Dima, Fusar-Poli, & Kyriakopoulos,
2014; van Erp et al., 2016; Voineskos, 2015). We have identified eight
structural brain imaging studies (Cousijn et al., 2014; Kelly et al., 2014;
Kuswanto et al., 2015; Lett et al., 2013; Li & Su, 2013; Patel et al., 2015;
Rose et al., 2014; Wright et al., 2016) that specifically tested for an
association between brain structure and variation in MIR137 (primarily the
risk tagging SNP rs1625579). Kuswanto et al. (2015) found a significant
interaction between MIR137 genotype and white matter integrity in the
right orbitofrontal region of SCZ cases. Wright et al. (2016) found that SCZ
subjects homozygous for the MIR137 risk allele showed significant
decreases in occipital, parietal, and temporal lobe grey matter concentra-
tion. Lett et al. (2013) found that patients with the MIR137 risk genotype
had reduced white matter integrity throughout the brain, smaller
hippocampi, and larger lateral ventricles. The five other reports (Kelly
et al., 2014; Li & Su, 2013; Patel et al., 2015; Rose et al., 2014; Wright et al.,
2016) examined only healthy controls (with the exception of Rose et al.
(2014) and Patel et al. (2015) who also included cases) and no clear
association between the MIR137 variant and brain structure was found.
While the overall pattern of results are mixed and the number of studies is
small, there may be a trend toward MIR137 exerting a greater influence in
SCZ cases versus healthy controls.
Functional brain imaging studies have been also performed, most
examining effects of the MIR137 risk SNP rs1625579 in healthy controls
(Liu et al., 2014; Mothersill et al., 2014; van Erp et al., 2014; Whalley
et al., 2012). van Erp et al. (2014) found the risk genotype to be
associated with higher left DLPFC activation. Similarly, Liu et al. (2014)
showed that individuals homozygous for the risk allele exhibited
significantly higher functional connectivity between DLPFC and left
hippocampi than heterozygous individuals Further studies found that
homozygous risk allele carriers had increased functional connectivity
between the right amygdala and frontal regions (Mothersill et al., 2014)
and higher activity in the posterior right medial frontal gyrus, BA6
(Whalley et al., 2012). Although most of these studies used healthy
controls, the results nonetheless demonstrate that individuals carrying
MIR137 risk alleles tend to have higher activity in some brain areas.
In sum, despite relatively small sample sizes and the genotyping of
only one MIR137 SCZ risk SNP, the existing brain imaging studies show
some promise. Recently, the ENIGMA consortium reported a genomic
association study for subcortical brain volume abnormalities in 2,028
SCZ and 2,540 healthy individuals (van Erp et al., 2016). This initial
subcortical-focused study did not find any association with MIR137,
but larger studies incorporating cortical measures are underway.
13 | P O T E N T I A L F O R C L I N I C A L U T I L I T Y
MicroRNAs are emerging as useful biomarkers and targets for therapeutic
manipulation in complex diseases. Circulating miRNA levels in plasma,
serum, and whole blood have shown potential as biomarkers of many
disorders (Kawaguchi et al., 2016; Kosaka, Iguchi, & Ochiya, 2010; Witwer,
2015) including SCZ (Cairns, 2015; Kichukova, Popov, Ivanov, & Vachev,
2015; Wang, Wang, Yang, & Huang, 2014). miR-137 has also been
suggested as a biomarker of brain cancers and Parkinson’s disease (Koshkin,
SAKAMOTO AND CROWLEY
Chistyakov, Nikitin, Konovalov, Potapov, Usachyov et al., 2014; Li et al.,
2016, 2017). Interestingly, Wu et al. (2016) recently demonstrated that miR-
137 levels in peripheral blood cells may have potential for diagnosing early
onset SCZ, though replication of this finding is needed. miR-137
transcription is regulated by the upstream hypomethylated CpG region
(Kozaki et al., 2008; Song et al., 2013), suggesting that DNA methylation
status may be another potential biomarker (Gao, Zhang, Breitling, &
Brenner, 2016; Henriksen, Madsen, Krarup, & Thorlacius-Ussing, 2015;
Kozaki et al., 2008). However, methylome-wide association studies of SCZ
using blood cell DNA have not shown a significant association with miR-137
(Aberg et al., 2014; Dempster et al., 2011).
Since miR-137 is known to modulate brain function, methods that
manipulate miR-137 expression could have therapeutic potential in
schizophrenia. miRNAs have been studied as a target of medications,
and some specific miRNA modulators are currently being studied
clinically. For example, antagomir-122, a chemically-modified anti-
sense miR-122, is in Phase2 clinical trials for treating infection with
hepatitis C virus (Lanford et al., 2010). Likewise, a miR-21 inhibitor is
undergoing a Phase1 trial for treatment of Alport syndrome, a kidney
disease with no currently-approved therapy (Gomez et al., 2015). In
addition, MRX34, a double-stranded mimic of the naturally occurring
tumor suppressor miR-34a, is being tested in a Phase1 trial for use with
advanced solid tumors (Beg et al., 2014).
It is theoretically possible that manipulating miR-137 expression with a
chemically modified miR-137 inhibitor or mimic could have utility in SCZ.
There are, however, technical challenges that must be addressed, including
achieving cell-type specificity and penetrating the blood-brain barrier
(Krutzfeldt et al., 2005; Price & Chen, 2014; van Rooij, Purcell, & Levin, 2012;
Zhang, Wang, & Gemeinhart, 2013). To overcome both of these challenges
simultaneously, virus-mediated delivery of a miR-137 modulator represents
a compelling strategy. Working toward this goal, Murlidharan et al. (2016)
recently established a neuron-specific adeno-associated virus capable of
exclusively delivering a MIR137 specific guide RNA to neuronal cells for
CRISPR/Cas9-targeted genome editing. Since, intravenous AAV injection
can deliver genes to the brain (Murlidharan, Samulski, & Asokan, 2014;
Schuster et al., 2014; Shen et al., 2013), this strategy could be useful for the
manipulation of miR-137 activity by delivering a miR-137 overexpression
vector, an antisense inhibitor, or a MIR137 specific guide RNA capable of
recruiting artificial transcription regulators (e.g., dCas9-VP16/–KRAB) to the
MIR137 promoter in the neuronal cell (Genga, Kearns, & Maehr, 2016; Vora,
Tuttle, Cheng, & Church, 2016).
14 | C O N C L U S I O N S AN D S U GG E S TI O N S
FO R FU TU R E RE S E A R C H
We have attempted to comprehensively review the genetic and
biological evidence supporting a role for miR-137 in the etiology of
SCZ. We conclude that the evidence is strong, but mechanistic details
are lacking and, since SCZ is highly polygenic, at the level of the
individual miR-137’s role may be small. As noted in this review,
however, miR-137 clearly regulates a number of other SCZ risk genes
and therefore may represent an important signaling node within one or
| 9
more SCZ-related gene networks. Without question, there is ample
evidence to continue pursuing this gene and its associated network.
We believe that further investigations in several key areas are
needed to fully appreciate the role of MIR137 in SCZ and test its
diagnostic and therapeutic potential. First, on the genetic level, we
suggest that future GWAS studies move beyond the case-control
design, toward a “deep-phenotyping” symptom-dimension approach,
integrating neurocognitive measures, environmental factors, etc as
proposed by other investigators (Ehrenreich et al., 2016; Insel et al.,
2010). Second, on the molecular level, we think it is very important to
definitively identify the causal genetic variant(s) underlying the SCZ
GWAS association. As noted above, the last few years have witnessed
marked progress in this area, but ever more advanced molecular
methods are now available and could yield major insights. For example,
allele-specific RNA sequencing in the brains of individuals heterozy-
gous for SCZ-risk variants could clarify the direction of effect in this
locus. Critically, these sequencing efforts should distinguish the host
gene (MIR137HG) from the pre-miRNA and final, processed miRNA to
tease apart transcriptional and post-transcriptional effects. Further-
more, these studies likely need to be performed across developmental
stages and distinct cell types (e.g., using single-cell methods) to yield
the most informative data. Third, the role of miR-137 in glial cells has
been somewhat neglected in the pathological and non-pathological
state, particularly given its role as a tumor suppressor in glioblastoma.
Fourth, given that human brain tissue is generally inaccessible, we
believe improved genetic animal models will be a required to truly
understand miR-137 from a mechanistic level. For example, given the
embryonic lethality of the constitutive knockout mouse, there is an
urgent need for a conditional knockout. Fifth, and finally, we suggest
work toward improving methods for miR-137 manipulation in live
animals to gauge utility as a therapeutic target and biomarker. These
might include, for example, the development of brain-penetrating
antagomirs, enhanced CRISPR/Cas9 mediated manipulation protocols
or small molecules with specific effects on the miR-137 network. In
conclusion, MIR137 remains a prominent SCZ risk gene with potential
to open a window into the complex etiology of SCZ as the field works
toward developing novel treatments for this devastating disorder.
ACKNOWLEDGMENTS
The authors wish to thank Drs. Patrick Sullivan, Jin Szatkiewicz, and
Praveen Sethupathy for helpful discussions. Dr. Sakamoto was supported
by NIH grants R21MH099370 and R21MH102814. Dr. Crowley is
supported by NIH grants R01MH105500 and R01MH110427.
CONFLICT OF I NTEREST
The authors have no interests to disclose.
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How to cite this article: Sakamoto K, Crowley JJ.
A comprehensive review of the genetic and biological
evidence supports a role for MicroRNA-137 in the etiology
of schizophrenia. Am J Med Genet Part B. 2017;9999:1–15.
https://doi.org/10.1002/ajmg.b.32554