Elucidation of the molecular network that controls myelination

• Project/Area Number: 17K07127
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Miyamoto Yuki 国立研究開発法人国立成育医療研究センター, 薬剤治療研究部, 研究員 (50425708)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ミエリン / オリゴデンドロサイト / 共培養 / ミエリン変性症 / グリア細胞

Outline of Final Research Achievements

During development of the nervous system in mammals, myelin-forming cells wrap their plasma membranes around neuronal axons, forming multiple myelin sheaths. Arf1 is a small guanosine triphosphate-binding protein that plays multiple roles in intracellular trafficking and related signaling, We demonstrate that the Arf1 guanine nucleotide exchange factor, BIG1, and the effector Arf1 regulate the initiation of myelination of axons by Schwann cells. Schwann cell-specific BIG1 conditional knockout mice, which have been generated here, exhibit reduced myelin thickness and decreased localization of myelin protein zero in the myelin membrane, compared with their littermate controls. Similar results in myelin thickness are observed in Arf1 conditional knockout mice, which have also been generated here. Thus, the BIG1 and Arf1 unit plays a key role in Schwann cell myelination, newly adding it to the list of molecular units controlling myelination.

Academic Significance and Societal Importance of the Research Achievements

神経科学の分野で、ミエリン形成細胞を対象とした研究は国内外において非常に少ない。しかし、近年、筋萎縮性側索硬化症やアルツハイマー型認知症においてミエリン構造の異常が明らかとなってきたように、今後神経変性症などの創薬ターゲットとしてミエリン形成細胞が脚光を浴びることは想像に難くない。本研究では、研究人口の少ないミエリン形成細胞を対象とし、中でも未知の部分が多いミエリン発生期を司る分子機構について研究を行ったものである。

Research Products

• [Journal Article] Cellular signal-regulated Schwann cell myelination and remyelination. (2019)
  • Author(s): Tomohiro Torii, Yuki Miyamoto, and Junji Yamauchi
  • Journal Title: Adv. Exp. Med. Biol. Volume: 1190 Pages: 3-22
  • DOI: 10.1007/978-981-32-9636-7_1
  • ISBN: 9789813296350, 9789813296367
  • Peer Reviewed
• [Journal Article] Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation. (2019)
  • Author(s): Matsumoto N, Watanabe N, Iibe N, Tatsumi Y, Hattori K, Takeuchi Y, Oizumi H, Ohbuchi K, Torii T, Miyamoto Y, Yamauchi J.
  • Journal Title: Biochem Biophys Rep. Volume: 20 Pages: 100705-100705
  • DOI: 10.1016/j.bbrep.2019.100705
  • Peer Reviewed / Open Access
• [Journal Article] Data on the effects of Charcot-Marie-Tooth disease type 2N-associated AARS missense mutation (Arg329-to-His) on the cell biological properties. (2019)
  • Author(s): Imaizumi N, Takeuchi Y, Hirano H, Torii T, Seki Y, Morimoto T, Miyamoto Y, Sakagami H, Yamauchi J.
  • Journal Title: Data Brief Volume: 25 Pages: 104029-104029
  • DOI: 10.1016/j.dib.2019.104029
  • Peer Reviewed / Open Access
• [Journal Article] CMT type 2N disease-associated AARS mutant inhibits neurite growth that can be reversed by valproic acid (2019)
  • Author(s): Tatsumi Yuriko、Matsumoto Naoto、Iibe Noriko、Watanabe Natsumi、Torii Tomohiro、Sango Kazunori、Homma Keiichi、Miyamoto Yuki、Sakagami Hiroyuki、Yamauchi Junji
  • Journal Title: Neuroscience Research Volume: 139 Pages: 69-78
  • DOI: 10.1016/j.neures.2018.09.016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Defective neuronal and oligodendroglial differentiation by FTD3- and ALS17-associated Ile29-to-Val mutation of CHMP2B. (2019)
  • Author(s): Minami Yamawaki, Masumi Akiba, Naoto Matsumoto, Natsumi Watanabe, Kohei Hattori, Yu Takeuchi, Takako Morimoto, Hiroaki Oizumi, Katsuya Ohbuchi, Yuki Miyamoto, and Junji Yamauchi
  • Journal Title: Mol. Genet. Metab. Rep. Volume: 19 Pages: 100458-100458
  • DOI: 10.1016/j.ymgmr.2019.100458
  • Peer Reviewed / Open Access
• [Journal Article] Effects of HLD-associated POLR1C mutant proteins on cellular localization and differentiation. (2018)
  • Author(s): Hiraoka Y, Hattori K, Takeuchi Y, Yamawaki M, Watanabe N, Matsumoto N, Homma K, Miyamoto Y, Yamauchi J
  • Journal Title: Mol. Genet. Metab. Rep. Volume: 17 Pages: 80-82
  • DOI: 10.1016/j.ymgmr.2018.11.002
  • Peer Reviewed / Open Access
• [Journal Article] Pull down assay for GTP-bound form of Sar1a reveals its activation during morphological differentiation. (2018)
  • Author(s): Urai Y, Yamawaki M, Watanabe N, Seki Y, Morimoto T, Tago K, Homma K, Sakagami H, Miyamoto Y, Yamauchi J
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 503 Issue: 3 Pages: 2047-2053
  • DOI: 10.1016/j.bbrc.2018.07.157
  • Peer Reviewed
• [Journal Article] Data on the effect of knockout of neruregulin-1 type III on Remak bundle structure. (2018)
  • Author(s): Miyamoto Y, Torii T, Inoue M, Morimoto T, Yamamoto M, Yamauchi J
  • Journal Title: Data Brief Volume: 18 Pages: 803-807
  • DOI: 10.1016/j.dib.2018.03.099
  • Peer Reviewed / Open Access
• [Journal Article] BIG1/Arfgef1 and Arf1 regulate the initiation of myelination by Schwann cells in mice. (2018)
  • Author(s): Miyamoto Y, Torii T, Tago K, Tanoue A, Takashima S, Yamauchi J
  • Journal Title: Sci Adv. Volume: 4 Issue: 4
  • DOI: 10.1126/sciadv.aar4471
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Treacher Collins syndrome 3 (TCS3)-associated POLR1C mutants are localized in the lysosome and inhibits chondrogenic differentiation. (2018)
  • Author(s): Matsumoto N, Kaneko M, Watanabe N, Itaoka M, Seki Y, Morimoto T, Torii T, Miyamoto Y, Keiichi Homma, Yamauchi J
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 499 Issue: 1 Pages: 78-85
  • DOI: 10.1016/j.bbrc.2018.03.136
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The promoter region of 46-kDa CNPase is sufficient for its expression in corpus callosum. (2018)
  • Author(s): Miyamoto Y, Torii T, Tanoue A, Yamamoto M, Yamauchi J
  • Journal Title: Mol. Genet. Metab. Rep. Volume: 15 Pages: 78-79
  • DOI: 10.1016/j.ymgmr.2018.03.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dystonia-4 (DYT4)-associated TUBB4A mutants exhibit disorganized microtubule networks and inhibit neuronal process growth. (2018)
  • Author(s): Watanabe N, Itakaoka M, Seki Y, Morimoto T, Homma K, Miyamoto Y, Yamauchi J
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 495 Issue: 1 Pages: 346-352
  • DOI: 10.1016/j.bbrc.2017.11.038
  • Peer Reviewed
• [Journal Article] Data on the effect of knockout of cytohesin-1 in myelination-related protein kinase signaling. (2017)
  • Author(s): Ruri Tsuneishi, Naoto Matsumoto, Misa Itaoka, Yuki Urai, Minami Kaneko, Natsumi Watanabe, Shou Takashima, Yoichi Seki, Takako Morimoto, Hiroyuki Sakagami, Yuki Miyamoto, and Junji Yamauchi
  • Journal Title: Data Brief. Volume: 15 Pages: 234-239
  • DOI: 10.1016/j.dib.2017.09.024
  • Peer Reviewed / Open Access
• [Journal Article] Data on the effect of in vivo knockdown using artificial ErbB3 miRNA on Remak bundle structure. (2017)
  • Author(s): Yuki Miyamoto, Tomohiro Torii, Kazuko Kawahara, Masashi Inoue, Takako Morimoto, Masahiro Yamamoto, and Junji Yamauchi
  • Journal Title: Data Brief. Volume: 12 Pages: 313-319
  • DOI: 10.1016/j.dib.2017.04.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Defective myelination in mice harboring hypomyelinating leukodystrophy-associated HSPD1 mutation. (2017)
  • Author(s): Yuki Miyamoto, Kazuko Kawahara, Tomohiro Torii, and Junji Yamauchi
  • Journal Title: Mol. Genet. Metab. Rep. Volume: 11 Pages: 6-7
  • DOI: 10.1016/j.ymgmr.2017.03.003
  • Peer Reviewed / Open Access
• [Journal Article] Neuregulin-1 type III knockout mice exhibit delayed migration of Schwann cell precursors. (2017)
  • Author(s): Miyamoto Y, Torii T, Tanoue A, Kawahara K, Arai M, Tsumura H, Ogata T, Nagao M, Terada N, Yamamoto M, Takashima S, Yamauchi J
  • Journal Title: Biochemical and Biophysical Research Communication, Volume: 486 Issue: 2 Pages: 506-513
  • DOI: 10.1016/j.bbrc.2017.03.074
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Data supporting the role of Fyn in embryonic sciatic nerve fasciculation. (2017)
  • Author(s): Tomohiro Torii, Yuki Miyamoto, Kazuko Kawahara, Akito Tanoue, Yoichi Seki, Takako Morimoto, Masahiro Yamamoto, and Junji Yamauchi
  • Journal Title: Data Brief. Volume: 11 Pages: 358-363
  • DOI: 10.1016/j.dib.2017.02.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Data on the effect of hypomyelinating leukodystrophy 6 (HLD6)-associated mutations on the TUBB4A properties. (2017)
  • Author(s): Yuki Miyamoto, Tomohiro Torii, Kazuko Kawahara, Nanami Hasegawa, Akito Tanoue, Yoichi Seki, Takako Morimoto, Megumi Funakoshi-Tago, Hiroomi Tamura, Keiichi Homma, Masahiro Yamamoto, and Junji Yamauchi
  • Journal Title: Data Brief. Volume: 11 Pages: 284-289
  • DOI: 10.1016/j.dib.2017.02.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differentiation of oligodendrocyte progenitor cells from dissociated monolayer and feeder-free cultured pluripotent stem cells. (2017)
  • Author(s): Tomoko Yamashita, Yuki Miyamoto Yoshio Bando, Takashi Ono, Sakurako Kobayashi, Ayano Doi, Toshihiro Araki, Yosuke Kato, Takayuki Shirakawa, Yutaka Suzuki, Junji Yamauchi, Shigetaka Yoshida, and Naoya Sato
  • Journal Title: PLoS One. Volume: 12 Issue: 2 Pages: e0171947-e0171947
  • DOI: 10.1371/journal.pone.0171947
  • Peer Reviewed / Open Access
• [Presentation] BIG1/Arfgef1 and Arf1 regulate the initiation of myelination by Schwann cells in mice. (2019)
  • Author(s): 宮本幸、山内淳司
  • Organizer: 日本神経科学会・日本神経化学会合同年会
  • Invited
• [Presentation] 血管系にのみ発現するとされていた細胞接着因子による、新しい動的なミエリン（髄鞘）の形成メカニズム (2018)
  • Author(s): 宮本幸、山内淳司
  • Organizer: 第41回 日本神経科学大会
  • Invited
• [Presentation] alpha1インテグリンリガンドとVCAM1受容体による中枢神経系ミエリン形成機構 (2017)
  • Author(s): 宮本幸、山内淳司
  • Organizer: 生命科学系学会合同年次大会（ConBio2017）
• [Presentation] VCAM1 regulates oligodendrocyte myelination (2017)
  • Author(s): 山内淳司、宮本幸
  • Organizer: 日本神経化学会
• [Presentation] VCAM1がオリゴデンドロサイトのミエリン形成を制御する (2017)
  • Author(s): 宮本幸、山内淳司
  • Organizer: 日本ミエリン研究会