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Inositol-metabolizing enzyme gene-manipulated mice towards molecular dissection of pathophysiology of mental disorders.

Research Project

Project/Area Number 17390323
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionRIKEN

Principal Investigator

YOSHIKAWA Takeo  RIKEN, Lab.for Molecular Psychiatry, Team Reader, 分子精神科学研究チーム, チームリーダー (30249958)

Co-Investigator(Kenkyū-buntansha) OHNISHI Tetsuo  RIKEN, Lab. for Mol. Psychiatry, Researcher, 分子精神科学研究チーム, 研究員 (80373281)
YAMADA Kazuo  RIKEN, Lab. for Mol. Psychiatry, Researcher, 分子精神科学研究チーム, 研究員 (10322695)
IWAYAMA Yoshimi  RIKEN, Lab. for Mol. Psychiatry, Research Associate, 分子精神科学研究チーム, リサーチアソシエイト (60399441)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥15,600,000 (Direct Cost: ¥15,600,000)
Fiscal Year 2006: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥11,900,000 (Direct Cost: ¥11,900,000)
Keywordslithium / Impa1 / Impa2 / mood stabilizer / bipolar disorder / gene manipulated mice / IMPase / inositol / 統合失調症 / 熱性けいれん / モデルマウス / ENU / inositol monophosphatase / ノックアウトマウス / gene-driven mutagenesis / トランスジェニックマウス
Research Abstract

In this study, we successfully developed mice with manipulated genes for IMPase (inositol monophosphatase) : Impa1-Tg, Impa2-Tg, Impa1-ENU and Impa2-KO mice. Among them, transgenic mice with brain-specific IMPA2 overexpression exhibited moderate anxiety phenotype when evaluated in elevated plus maze (EPM) and light and dark (LD) box tests. Our analysis showed that at least one of three Impa1-ENU lines, where a missense mutation is introduced by a mutagen ENU (ethyl-nitroso-urea) at different position in the coding region of Impal gene, completely losses the enzymatic activity given by the Impal protein.
Our study also showed that a promoter haplotype of IMPA2 confers a possible risk for bipolar disorder in Japanese population possibly by enhancing transcription. Taken together with phenotype of Impa2-Tg mice, these data strongly suggest the function of IMPA2 in the pathogenesis of mood disorders, in particular, bipolar disorder.
Moreover, we first proved that the IMPA2 protein exhibits IMPase activity in vitro. IMPA1 and IMPA2 show clearly different tissue distributions, and have different sensitivities to lithium. To obtain further insight for the IMPA2 gene product, we first revealed the crystal structure of this protein. While the overall structure of the IMPA2 protein is similar to that of IMPA1, which exhibits lithium-inhibitable strong IMPase activity, IMPA2 possesses more widely opened cavity than that of IMPA1. These observations imply a specific function of IMPA2 in the biochemical process(es) in the cell, possibly having specific in vivo substrate(s), which is different from that for IMPA1.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (19 results)

All 2007 2006 2005 Other

All Journal Article (19 results)

  • [Journal Article] Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1.2007

    • Author(s)
      Ohnishi T et al.
    • Journal Title

      J. Biol. Chem. 282

      Pages: 637-646

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Crystal structure of human myo-inositol monophosphatase 2 (IMPA2), the product of the putative susceptibility gene for bipolar disorder, schizophrenia and febrile seizures.2007

    • Author(s)
      Arai R et al.
    • Journal Title

      Proteins : Structure, Function, and Bioinformatics 67

      Pages: 732-742

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia.2007

    • Author(s)
      Yamada K et al.
    • Journal Title

      Proc. Natl. Acad. Sci. USA. 104

      Pages: 2815-2820

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients.2007

    • Author(s)
      Sadakata T et al.
    • Journal Title

      J. Clin. Invest. 117

      Pages: 931-943

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A promoter haplotype of inositol monophosphatase 2 gene (IMPA2) at 18p11.2 possibly confers risk for bipolar disorder by enhancing transcription.2007

    • Author(s)
      Ohnishi T et al.
    • Journal Title

      Neuropsychopharmacology Jan 24 [Epub ahead of print]

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1.2007

    • Author(s)
      Ohnishi T et al.
    • Journal Title

      Biol. Chem. 282

      Pages: 637-646

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Crystal structure of human myo-inositol monophosphatase 2 (IMPA2), the product of the putative susceptibility gene for bipolar disorder, schizophrenia and febrile2007

    • Author(s)
      Arai R et al.
    • Journal Title

      Proteins : Structure, Function, and Bioinformatics 67

      Pages: 732-742

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia.2007

    • Author(s)
      Yamada K et a1.
    • Journal Title

      Proc. Natl. Acad. Sci. USA. 104

      Pages: 2815-2820

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients.2007

    • Author(s)
      Sadakata T et al.
    • Journal Title

      Clin. Invest. 117

      Pages: 931-43

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Spatial expression patterns and biochemical properties distingUish a second myo-inositol monophosphatase IMPA2 from IMPA1.2007

    • Author(s)
      Ohnishi T et al.
    • Journal Title

      J. Biol. Chem. 282

      Pages: 637-646

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia.2006

    • Author(s)
      Ide M et al.
    • Journal Title

      J. Neurochem. 99

      Pages: 277-287

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder : relevance to neuronal network perturbation.2006

    • Author(s)
      Nakatani N et al.
    • Journal Title

      Hum. Mol. Genet. 15

      Pages: 1949-1962

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia2005

    • Author(s)
      Kato T et al.
    • Journal Title

      Molecular Psychiatry 10

      Pages: 1045-1055

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A promoter haplotype of inositol monophosphatase 2 gene (IMPA2) at 18p11.2 possibly confers risk for bipolar disorder by enhancing transcription.

    • Author(s)
      Ohnishi T et al.
    • Journal Title

      Neuropsychopharmacology (印刷中)(オンライン版で発表済み)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] seizures.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A promoter haplotype of inositol monophosphatase 2 gene (IMPA2) at 18p11.2 possibly confers risk for bipolar disorder by enhancing transcription.

    • Author(s)
      Ohnishi T et al.
    • Journal Title

      Neuropsychopharmacology (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Crystal structure of human myo-inositol monophosphatase 2 (IMPA2), the product of the putative susceptibility gene for bipolar disorder, schizophrenia and febrile seizures

    • Author(s)
      Arai R et al.
    • Journal Title

      Proteins : Structure, Function, and Bioinformatics (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Genetic analysis of the calcineurin pathway identifies the EGR family and specifically EGR3, as potential candidates in schizophrenia.

    • Author(s)
      Yamada K ea tl.
    • Journal Title

      Proc. Natl. Acad. Sci. USA (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Autistic-like phenotypes in CAPS2/CADPS2 knockout mice and aberrant CAPS2 splicing in autistic patients.

    • Author(s)
      Sadakata T et al.
    • Journal Title

      J. Clin. Invest. (in press)

    • Related Report
      2006 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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