Transcriptional targets of the schizophrenia risk gene MIR137

Abstract

Genome-wide association studies (GWAS) have strongly implicated MIR137 (the gene encoding the microRNA miR-137) in schizophrenia. A parsimonious hypothesis is that a pathway regulated by miR-137 is important in the etiology of schizophrenia. Full evaluation of this hypothesis requires more definitive knowledge about biological targets of miR-137, which is currently lacking. Our goals were to expand knowledge of the biology of miR-137 by identifying its empirical targets, and to test whether the resulting lists of direct and indirect targets were enriched for genes and pathways involved in risk for schizophrenia. We overexpressed miR-137 in a human neural stem cell line and analyzed gene expression changes at 24 and 48 h using RNA sequencing. Following miR-137 overexpression, 202 and 428 genes were differentially expressed after 24 and 48 h. Genes differentially expressed at 24 h were enriched for transcription factors and cell cycle genes, and differential expression at 48 h affected a wider variety of pathways. Pathways implicated in schizophrenia were upregulated in the 48 h findings (major histocompatibility complex, synapses, FMRP interacting RNAs and calcium channels). Critically, differentially expressed genes at 48 h were enriched for smaller association P-values in the largest published schizophrenia GWAS. This work provides empirical support for a role of miR-137 in the etiology of schizophrenia.

MicroRNA-137 Controls AMPA-Receptor-Mediated Transmission and mGluR-Dependent LTD

“…However, we cannot exclude that molecular changes induced by altering miR-137 also could impact directly AMPAR trafficking or actin cytoskeleton dynamics. Of note, previous gene ontology (GO) analysis of the transcriptome data (Collins et al, 2014) suggests that the actin-remodeling pathway, including the Rho GTPase pathway (Govek et al, 2005), is a prominent signaling pathway that is targeted by miR-137. This is of interest since neuronal plasticity requires both actin cytoskeleton remodeling and local protein translation in response to extracellular signals (Zukin et al, 2009).…”

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

“…52 Actin-binding proteins, including Parvb and Dock1, but also Filamins, Talin and Fermt2 regulate actin polymerization, stabilization, elongation and branching. 42, 53, 54 Reorganizations of the actin cytoskeleton are essential for memory formation since they underlie the modulation of events such as presynaptic vesicle movement, postsynaptic glutamate receptors trafficking and dendritic spines morphogenesis. 42 Altered expression of miR-137 could as such impair neuronal and synaptic functioning, contributing to the cognitive deficits in associated integrity of neuronal networks in neuropathology.…”

MIR137 is the key gene mediator of the syndromic obesity phenotype of patients with 1p21.3 microdeletions

“…miR-137 is a brain expressed miRNA [17, 18] that regulates several protein coding genes that are important for brain function, and involved in the pathogenesis of neuropsychiatric disorders including schizophrenia [17, 19]. Functional studies indicate that miR-137 is involved in controlling neuronal differentiation and maturation [20, 21] as well as synapse development [22], all of which have been implicated on the pathogenesis of autism [20, 23]. Of note, lymphoblastoid cell lines from patients carrying 1p21.3 deletion involving the miR-137 gene have reduced levels of miR-137 [4].…”