Elucidation of the molecular mechanisms underlying the coupling between transcription and RNA metabolism during myelination

• Project/Area Number: 17K15542
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General anatomy (including histology/embryology)
• Research Institution: Niigata University
• Principal Investigator: Bizen Norihisa 新潟大学, 医歯学系, 助教 (40751053)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: オリゴデンドロサイト / ミエリン / 転写 / RNA代謝 / Olig2 / RNA / スプライシング / 脱髄 / 軸索変性 / ノックアウトマウス / 脱髄疾患 / 分化

Outline of Final Research Achievements

Oligodendrocytes (OLs) form the myelin sheaths around axons and regulate the axonal conduction in central nervous system (CNS). We have identified a novel Olig2-binding factor Obp2, which is involved in the transcription regulation and RNA metabolism. To elucidate the role of Obp2 in the myelination, we generated mature OL-specific Obp2 deficient mice (Mbp2-cre: Obp2 cKO). OL differentiation and myelinization are significantly suppressed in the spinal cords of Obp2-deficient mice. RNA-seq detected the abnormal splicing of OL-related factors. In addition, we found that the expression of snRNAs, which are main components of spliceosome, was significantly suppressed in Obp2-deficient spinal cord. Furthermore, the C-terminal region of Obp2, which binds to Olig2, promoted the activation of OL-related gene promoters. Thus, these results suggest that Obp2 is a key regulator for OL differentiation and myelination through RNA splicing and transcriptional regulation.

Academic Significance and Societal Importance of the Research Achievements

本研究によりObp2は転写調節のみならずRNAヘリカーゼとしてRNA代謝の様々なステップに関与することが考えられ、OL分化およびミエリン形成の新たな制御機構として重要な分子であることがわかった。転写からRNA代謝へのプロセスは生命現象の根幹であり、本研究の成果は、ミエリン形成だけに限らず、生体における生理機構全般に当てはまる新たな仕組みとして提示できるため学術的に有意義である。また、ミエリン構造の破綻が起因となる神経疾患は、従来の脱髄疾患やミエリン形成不全症のみならず、統合失調症などの精神疾患にも及ぶ可能性があり、本研究の成果は治療法確立の観点において社会的意義も大きいと考えられる。

Research Products

• [Journal Article] Diverse mutations in dystonin gene cause distinct patterns of Dst isoform deficiency and phenotypic heterogeneity in dystonia musculorum mice. (2020)
  • Author(s): Yoshioka N, Kabata Y, Kuriyama M, Bizen N, Zhou L, Tran MD, Yano M, Yoshiki A, Ushiki T, Sproule TJ, Abe R, Takebayashi H
  • Journal Title: Disease Models and Mechanisms Volume: 13 Issue: 5 Pages: 041608-041608
  • DOI: 10.1242/dmm.041608
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Olig2 regulates terminal differentiation and maturation of peripheral olfactory sensory neurons (2019)
  • Author(s): Wang YZ, Fan H, Ji Y, Reynolds K, Gu R, Gan Q, Yamagami T, Zhao T, Hamad S, Bizen N, Takebayashi H, Chen Y, Wu S, Pleasure D, Lam K, Zhou CJ
  • Journal Title: Cellular and Molecular Life Sciences Volume: - Issue: 18 Pages: 3597-3609
  • DOI: 10.1007/s00018-019-03385-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model. (2019)
  • Author(s): Terumitsu-Tsujita M, Kitaura H, Miura I, Kiyama Y, Goto F, Muraki Y, Ominato S, Hara N, Simankova A, Bizen N, Kashiwagi K, Ito T, Toyoshima Y, Kakita A, Manabe T, Wakana S, Takebayashi H, Igarashi H
  • Journal Title: Ｊｏｕｒｎａｌ ｏｆ Ｎｅｕｒｏｃｈｅｍｉｓｔｒｙ Volume: jnc.14887 Issue: 1 Pages: 1-16
  • DOI: 10.1111/jnc.14887
  • Peer Reviewed / Open Access
• [Presentation] 新規Olig2結合因子による神経前駆細胞およびオリゴデンドロサイト前駆細胞維持機構の解明 (2020)
  • Author(s): 備前典久, 矢野真人, 周麗, 阿部学, 崎村建司, 竹林浩秀
  • Organizer: 第125回日本解剖学会総会全国学術集会
• [Presentation] Mice lacking a novel Olig2-binding factor displays the attenuation of oligodendrocyte differentiation and myelination in the central nervous system (2020)
  • Author(s): Norihisa Bizen, Anna Simankova, Nobuhiko Ohno, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi
  • Organizer: ABiS international symposium
• [Presentation] Elucidation of the mechanisms underlying a novel Olig2 binding factor-mediated maintenance of oligodendrocyte precursor cells (2019)
  • Author(s): Norihisa Bizen, Masato Yano, Zhou Li, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi
  • Organizer: IBRO 2019
  • Int'l Joint Research
• [Presentation] Identification of a novel Olig2-binding factor indispensable for the maintenance of oligodendrocyte precursor cells in the central nervous system (2019)
  • Author(s): Norihisa Bizen, Masato Yano, Anna Simankova, Li Zhou, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi
  • Organizer: Neuro 2019
• [Presentation] Analysis of the Effect of a Novel Olig2-Binding Factor on the Oligodendrocyte Differentiation and Myelination in Central Nervous System (2019)
  • Author(s): Norihisa Bizen, Anna Simankova, Nobuhiko Ohno, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi
  • Organizer: The 66th NIBB Conference -ABiS International Symposium-
• [Presentation] 新規Olig2結合因子によるオリゴデンドロサイト前駆細胞維持機構の解明 (2019)
  • Author(s): 備前典久、矢野真人、周麗、阿部学、崎村建司、竹林浩秀
  • Organizer: 第124回日本解剖学会総会全国学術集会
• [Presentation] 新規Olig2結合因子によるオリゴデンドロサイト発生機構の解析 (2018)
  • Author(s): 備前典久、矢野真人、周麗、崎村建司、竹林浩秀
  • Organizer: 第23回グリアクラブ
• [Presentation] 新規Olig2結合因子によるオリゴデンドロサイト発生機構の解明 (2018)
  • Author(s): 備前典久、矢野真人、周麗、崎村建司、竹林浩秀
  • Organizer: 第123回日本解剖学会総会全国学術集会
• [Presentation] Identification of a novel Olig2-binding factor indispensable for oligodendrogenesis in central nervous system (2017)
  • Author(s): Norihisa Bizen, Masato Yano, Zhou Li, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi
  • Organizer: 次世代脳プロジェクト 冬のシンポジウム