The schizophrenia risk gene MIR137 acts as a hippocampal gene network node orchestrating the expression of genes relevant to nervous system development and function

Abstract

MicroRNAs (miRs) are small regulatory molecules, which orchestrate neuronal development and plasticity through modulation of complex gene networks. microRNA-137 (miR-137) is a brain-enriched RNA with a critical role in regulating brain development and in mediating synaptic plasticity. Importantly, mutations in this miR are associated with the pathoetiology of schizophrenia (SZ), and there is a widespread assumption that disruptions in miR-137 expression lead to aberrant expression of gene regulatory networks associated with SZ. To systematically identify the mRNA targets for this miR, we performed miR-137 gain- and loss-of-function experiments in primary rat hippocampal neurons and profiled differentially expressed mRNAs through next-generation sequencing. We identified 500 genes that were bidirectionally activated or repressed in their expression by the modulation of miR-137 levels. Gene ontology analysis using two independent software resources suggested functions for these miR-137-regulated genes in neurodevelopmental processes, neuronal maturation processes and cell maintenance, all of which known to be critical for proper brain circuitry formation. Since many of the putative miR-137 targets identified here also have been previously shown to be associated with SZ, we propose that this miR acts as a critical gene network hub contributing to the pathophysiology of this neurodevelopmental disorder.

Effects of MiR‐137 genetic risk score on brain volume and cortical measures in patients with schizophrenia and controls

“…In silico and in vitro studies looking at the downstream effects of microRNA‐137 have predicted or shown it to impact on the regulation of other genes linked to psychosis (Collins et al, ; Hill et al, ; Wright, Turner, Calhoun, & Perrone‐Bizzozero, ). In a study performed to characterize the regulatory effects of miR‐137, under‐expression of miR‐137 led to a general upregulation of many genes, with the opposite shown in overexpression (Olde Loohuis et al, ). Risk alleles of four SZ‐associated SNPs in the region of MIR137 (rs1198588, rs1625579, rs2660304, and rs2802535) have been associated with downregulation of miR‐137, specific to neuronal cells (Siegert et al, ).…”

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

“…We also noted a variant (rs534059912) in the GOLM1 gene (Golgi membrane protein 1), which was earlier reported in sporadic Alzheimer's dementia (AD) to influence the pre‐frontal cortical volume . A list of these 10 genes, evidence for disease association, and gene ontology descriptions are presented in Table (b) …”

“…43 A list of these 10 genes, evidence for disease association, and gene ontology descriptions are presented in Table 2(b). [44][45][46][47][48][49][50][51][52] Of the remaining genes, there were several with a plausible role in the biology of SMI, but not thus far implicated in any disease phenotype. These genes, with the ontology descriptions and plausible biological implications, are provided in Table 2(c).…”

Weighted burden analysis of exome-sequenced case-control sample implicates synaptic genes in schizophrenia aetiology

“…It should be noted that different sets might be implicated for different reasons. For example, it may be that the high SLP for targets of miR-137 occurs because disruption of the regulation of these genes by miR-137 can lead to increased risk of schizophrenia, as supported by the association of schizophrenia with markers for miR-137 and with variants in its binding sites (Curtis and Emmett, 2017;Olde Loohuis et al, 2017). On the other hand, there is no reported association of FMRP itself with schizophrenia and the high SLP for its targets may simply reflect that this identifies a group of genes whose mRNA is localised to the synapse.…”