title: 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.
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, 6500 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, The Netherlands.
authors.forename: Nikkie F M
authors.initials: NF
authors.lastname: Olde Loohuis
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, 6500 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, The Netherlands; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, The Netherlands.
authors.forename: Nael
authors.initials: N
authors.lastname: Nadif Kasri
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, 6500 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, The Netherlands.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Glennon
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, 6500 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, The Netherlands; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, CHUL, Québec, QC G1V4G2, Canada; Département de psychiatrie et neurosciences, Université Laval, Québec, QC G1V 0A6, Canada.
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
authors.affiliation: Laboratory of Molecular Biology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Barry B
authors.initials: BB
authors.lastname: Kaplan
authors.affiliation: Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, The Netherlands; Department of Molecular Animal Physiology, Radboud University Nijmegen, 6525 HP Nijmegen, The Netherlands.
authors.forename: Gerard J M
authors.initials: GJ
authors.lastname: Martens
authors.affiliation: Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, The Netherlands; Laboratory of Molecular Biology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: armaz.aschrafi@nih.gov.
authors.forename: Armaz
authors.initials: A
authors.lastname: Aschrafi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000235:genetics; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009420:Nervous System / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000235:genetics*; D014162:Transfection
chemical_list: C545567:MIRN137 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger
keywords: Gene network; MicroRNA; Neurodevelopment