Elucidation of the molecular basis of miRNAs related to neurodevelopmental disorders of schizophrenia

• Project/Area Number: 15K09849
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: toyoshima manabu 国立研究開発法人理化学研究所, 脳科学総合研究センター, 研究員 (90582750)
• Co-Investigator(Kenkyū-buntansha): 吉川 武男 国立研究開発法人理化学研究所, その他, 研究員 (30249958)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 統合失調症 / miRNA / 神経発達 / iPS細胞 / 神経分化 / 22q11.2欠失 / DGCR8

Outline of Final Research Achievements

We established hiPSCs from two schizophrenia patients with the 22q11.2 deletion, and examined the molecular pathology of microRNA (miRNA) related to abnormality of neuronal differentiation/development. Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38, and conformingly the levels of p38 were up-regulated in the patient-derived cells. Furthermore, we confirmed an elevated expression of gliogenic (astrocyte) marker in postmortem brains from schizophrenia patients. These results suggest that a dysregulated balance of neurogenic and gliogenic competences may underlie schizophrenia.

Research Products

• [Journal Article] Contribution of induced pluripotent stem cell technologies to the understanding of cellular phenotypes in schizophrenia. (2018)
  • Author(s): Balan S, Toyoshima M, Yoshikawa T
  • Journal Title: Neurobiology of Disease Volume: 印刷中 Pages: 104162-104162
  • DOI: 10.1016/j.nbd.2018.04.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of induced pluripotent stem cells carrying 22q11.2 deletion (2016)
  • Author(s): Toyoshima M, Akamatsu W, Okada Y, Ohnishi T, Balan S, Hisano Y, Iwayama Y, Toyota T, Matsumoto T, Itasaka N, Sugiyama S, Tanaka M, Yano M, Dean B, Okano H, Yoshikawa T
  • Journal Title: Translational Psychiatry Volume: 6 Issue: 11 Pages: e934-e934
  • DOI: 10.1038/tp.2016.206
  • Peer Reviewed / Open Access
• [Journal Article] Functional Neurons Generated from T Cell-Derived Induced Pluripotent Stem Cells (2016)
  • Author(s): Matsumoto T, Fujimori K, Andoh-Noda T, Ando T, Kuzumaki N, Toyoshima M, Tada H, Imaizumi K, Ishikawa M, Yamaguchi R, Isoda M, Zhou Z, Sato S, Kobayashi T, Ohtaka M, Nishimura K, Kurosawa H, Yoshikawa T, Takahashi T, Nakanishi M, Ohyama M, Hattori N, Akamatsu W, Okano H.
  • Journal Title: Stem Cell Reports. Volume: 6 Issue: 3 Pages: 422-35
  • DOI: 10.1016/j.stemcr.2016.01.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism. (2015)
  • Author(s): Maekawa M, Iwayama Y, Ohnishi T, Toyoshima M, Shimamoto C, Hisano Y, Toyota T, Balan S, Matsuzaki H, Iwata Y, Takagai S, Yamada K, Ota M, Fukuchi S, Okada Y, Akamatsu W, Tsujii M, Kojima N, Owada Y, Okano H, Mori N, Yoshikawa T
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 16239-16239
  • DOI: 10.1038/srep16239
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia. (2015)
  • Author(s): Balan S, Iwayama Y, Yamada K, Toyota T, Ohnishi T, Toyoshima M, Shimamoto C, Ide M, Iwata Y, Suzuki K, Kikuchi M, Hashimoto T, Kanahara N, Yoshikawa T, Maekawa M.
  • Journal Title: J Neural Transm Volume: 122 Issue: 3 Pages: 477-485
  • DOI: 10.1007/s00702-014-1269-0
  • Peer Reviewed / Open Access
• [Journal Article] Utility of Scalp Hair Follicles as a Novel Source of Biomarker Genes for Psychiatric Illnesses. (2014)
  • Author(s): Maekawa M, Yamada K, Toyoshima M, Ohnishi T, Iwayama Y, Shimamoto C, Toyota T, Nozaki Y, Balan S, Matsuzaki H, Iwata Y, Suzuki K, Miyashita M, Kikuchi M, Kato M, Okada Y, Akamatsu W, Mori N, Owada Y, Itokawa M, Okano H, Yoshikawa T.
  • Journal Title: Biological Psychiatry Volume: 3223 Issue: 2 Pages: 00570-00578
  • DOI: 10.1016/j.biopsych.2014.07.025
  • NAID: 40020643113
  • Peer Reviewed / Open Access
• [Presentation] カルボニルストレスによる神経分化異常の分子病態 (2018)
  • Author(s): 豊島学, 大西哲生, 新井誠, 糸川昌成, 岡野栄之, 吉川武男
  • Organizer: 第13回日本統合失調症学会
• [Presentation] 患者由来のiPS細胞を用いた神経発達障害に関わるmiRNAの分子病態の解明 (2017)
  • Author(s): 豊島学, 赤松和土, 岡田洋平, 大西哲生, 岡野栄之, 吉川武男
  • Organizer: 第12回日本統合失調症学会
  • Place of Presentation: 米子コンベンションセンターBIG SHIP (鳥取県米子市)
  • Year and Date: 2017-03-23
• [Presentation] iPS細胞から見える統合失調症の病理と今後の発展 (2017)
  • Author(s): 豊島学, 赤松和土, 岡田洋平, 大西哲生, 新井誠, 糸川昌成, 岡野栄之, 吉川武男
  • Organizer: 第39回日本生物学的精神医学会
  • Invited
• [Presentation] GLO1遺伝子変異によるカルボニルストレスと神経分化異常の解析 (2017)
  • Author(s): 豊島学, 大西哲生, 新井誠, 糸川昌成, 岡野栄之, 吉川武男
  • Organizer: 第44回日本脳科学会
• [Presentation] Schizophrenia patient-derived hiPSCells exhibit changes in Neurogenic and Gliogenic Competences (2016)
  • Author(s): Manabu Toyoshima, Wado Akamatsu, Yohei Okada, Hideyuki Okano and Takeo Yoshikawa
  • Organizer: CINP 2016
  • Place of Presentation: 韓国、ソウル
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] 統合失調症患者由来神経幹細胞における分化異常の分子病態 (2016)
  • Author(s): 豊島学, 赤松和土, 岡田洋平, 大西哲生, 田中元雅, 岡野栄之, 吉川武男
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: 韓国、ソウル
  • Year and Date: 2016-07-02
  • Invited
• [Presentation] 22q11.2 欠失を伴った統合失調症患者由来神経幹細胞における分子病態解析 (2016)
  • Author(s): 豊島学, 赤松和土, 岡田洋平, 大西哲生, Shabeesh Balan, 田中元雅, 岡野栄之, 吉川武男
  • Organizer: 第11回日本統合失調症学会
  • Place of Presentation: ベイシア文化ホール（群馬）
  • Year and Date: 2016-03-25
• [Book] 遺伝子発現からみたうつ病の神経科学 (2016)
  • Author(s): 前川素子、豊島学、吉川武男
  • Total Pages: 232
  • Publisher: 最新医学社
• [Book] 統合失調症の神経発達障害にかかわるmiRNAの分子基盤 (2016)
  • Author(s): 豊島学、吉川武男
  • Total Pages: 65
  • Publisher: 先端医学社
• [Remarks] iPS細胞からみえる統合失調症の特徴
  • URL: http://www.riken.jp/pr/press/2016/20161102_1/digest/