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

2019 Fiscal Year Final Research Report

• 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
• Keywords: オリゴデンドロサイト / ミエリン / 転写 / RNA代謝 / Olig2

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.

Free Research Field

神経解剖学・神経発生学

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。