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Disruption of the MicroRNA 137 Primary Transcript Results in Early Embryonic Lethality in Mice

      Multiple lines of evidence support a role for microRNA 137 (miR-137) in the etiology of schizophrenia (
      Schizophrenia Working Group of the Psychiatric Genomics Consortium
      Genome-wide association study identifies five new schizophrenia loci.
      ,
      • Ripke S.
      • O’Dushlaine C.
      • Chambert K.
      • Moran J.L.
      • Kahler A.K.
      • Akterin S.
      • et al.
      Genome-wide association analysis identifies 13 new risk loci for schizophrenia.
      ,
      • van Erp T.G.
      • Guella I.
      • Vawter M.P.
      • Turner J.
      • Brown G.G.
      • McCarthy G.
      • et al.
      Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation.
      ,
      • Lett T.A.
      • Chakavarty M.M.
      • Felsky D.
      • Brandl E.J.
      • Tiwari A.K.
      • Goncalves V.F.
      • et al.
      The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia.
      ) and fundamental neuronal processes (
      • Szulwach K.E.
      • Li X.
      • Smrt R.D.
      • Li Y.
      • Luo Y.
      • Lin L.
      • et al.
      Cross talk between microRNA and epigenetic regulation in adult neurogenesis.
      ,
      • Smrt R.D.
      • Szulwach K.E.
      • Pfeiffer R.L.
      • Li X.
      • Guo W.
      • Pathania M.
      • et al.
      MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1.
      ,
      • Willemsen M.H.
      • Valles A.
      • Kirkels L.A.
      • Mastebroek M.
      • Olde Loohuis N.
      • Kos A.
      • et al.
      Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability.
      ). In the largest genome-wide association meta-analysis for schizophrenia (

      Schizophrenia Working Group of the Psychiatric Genomics Consortium (in press): Biological insights from 108 schizophrenia-associated genetic loci. Nature.

      ), the second most significant association is in MIR137HG, the gene encoding miR-137 (rs1702294; p = 3.4 × 10−19). Prior reports indicated that genes with predicted miR-137 target sites were enriched for smaller genome-wide association studies p values (
      • Ripke S.
      • O’Dushlaine C.
      • Chambert K.
      • Moran J.L.
      • Kahler A.K.
      • Akterin S.
      • et al.
      Genome-wide association analysis identifies 13 new risk loci for schizophrenia.
      ), raising the possibility that miR-137 regulates a gene network involved in schizophrenia. To understand more about the role of miR-137, we describe here our characterization of embryonic development, behavior, and gene expression in mice with targeted disruption of the Mir137 transcript (Supplement 1).
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      References

        • Schizophrenia Working Group of the Psychiatric Genomics Consortium
        Genome-wide association study identifies five new schizophrenia loci.
        Nat Genet. 2011; 43: 969-976
        • Ripke S.
        • O’Dushlaine C.
        • Chambert K.
        • Moran J.L.
        • Kahler A.K.
        • Akterin S.
        • et al.
        Genome-wide association analysis identifies 13 new risk loci for schizophrenia.
        Nat Genet. 2013; 45: 1150-1159
        • van Erp T.G.
        • Guella I.
        • Vawter M.P.
        • Turner J.
        • Brown G.G.
        • McCarthy G.
        • et al.
        Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation.
        Biol Psychiatry. 2014; 75: 398-405
        • Lett T.A.
        • Chakavarty M.M.
        • Felsky D.
        • Brandl E.J.
        • Tiwari A.K.
        • Goncalves V.F.
        • et al.
        The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia.
        Mol Psychiatry. 2013; 18: 443-450
        • Szulwach K.E.
        • Li X.
        • Smrt R.D.
        • Li Y.
        • Luo Y.
        • Lin L.
        • et al.
        Cross talk between microRNA and epigenetic regulation in adult neurogenesis.
        J Cell Biol. 2010; 189: 127-141
        • Smrt R.D.
        • Szulwach K.E.
        • Pfeiffer R.L.
        • Li X.
        • Guo W.
        • Pathania M.
        • et al.
        MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1.
        Stem Cells. 2010; 28: 1060-1070
        • Willemsen M.H.
        • Valles A.
        • Kirkels L.A.
        • Mastebroek M.
        • Olde Loohuis N.
        • Kos A.
        • et al.
        Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability.
        J Med Genet. 2011; 48: 810-818
      1. Schizophrenia Working Group of the Psychiatric Genomics Consortium (in press): Biological insights from 108 schizophrenia-associated genetic loci. Nature.

        • Park C.Y.
        • Jeker L.T.
        • Carver-Moore K.
        • Oh A.
        • Liu H.J.
        • Cameron R.
        • et al.
        A resource for the conditional ablation of microRNAs in the mouse.
        Cell Rep. 2012; 1: 385-391
        • Testa G.
        • Schaft J.
        • van der Hoeven F.
        • Glaser S.
        • Anastassiadis K.
        • Zhang Y.
        • et al.
        A reliable lacZ expression reporter cassette for multipurpose, knockout-first alleles.
        Genesis. 2004; 38: 151-158