Evaluation of a drug-target-molecule for demyelinating disorders using Dock7 knockdown mouse

2013 Fiscal Year Final Research Report

• Project/Area Number: 23650200
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: YAMAUCHI Junji 独立行政法人国立成育医療研究センター, 薬剤治療研究部, 室長 (20335483)
• Project Period (FY): 2011 – 2013
• Keywords: ミエリン形成 / 脱ミエリン現象 / 交換因子 / 低分子量GTP結合蛋白質 / 創薬標的分子 / 先天性疾患 / グリア細胞 / 人工組織構築

Research Abstract

During development of the peripheral nervous system (PNS), Schwann cells (SCs) wrap axons to form a multilamellar structure called myelin, which functions as an insulator surrounding axons. In peripheral neuropathies such as Charcot-Marie-Tooth (CMT) disease, chronic demyelination and defective remyelination are repeated, causing more severe neuropathies. It is thus thought that development of a drug that promotes healthy myelination, with minimal side effects, may lead to useful therapeutic methods for these diseases. However, specific therapeutic drug targets that healthily promote myelination have hitherto remained unclear. In this study, we generated new transgenic mice expressing shRNA for Dock7, which knocked down Dock7 protein levels. We describe that knockdown of Dock7 specifically promotes myelination in vivo and in vitro. To the best of our knowledge, this is the first report of a possible therapeutic target molecule that promotes myelination without reduced axon thickness.

Research Products

• [Journal Article] Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons (2013)
  • Author(s): Yuki Miyamoto, Tomohiro Torii, Natsuki Yamamori, Toru Ogata, Akito Tanoue, and Junji Yamauchi
  • Journal Title: Sci. Signal. (サイエンス姉妹誌) Volume: 6
  • DOI: 10.1126/scisignal.2003661
• [Journal Article] Phosphorylation of cytohesin-1 by Fyn is required for initiation of myelination and the extent of myelination during development (2012)
  • Author(s): Junji Yamauchi, Yuki Miyamoto, Tomohiro Torii, Shou Takashima, Kazumi Kondo, Katsumasa Kawahara, Noriko Nemoto, Jonah R. Chan, Gozoh Tsujimoto, and Akito Tanoue
  • Journal Title: Sci. Signal. (サイエンス姉妹誌) Volume: 5
  • DOI: 10.1126/scisignal.2002802
• [Journal Article] The atypical guanine-nucleotide exchange factor, Dock7, negatively regulates Schwann cell differentiation and myelination (2011)
  • Author(s): Junji Yamauchi, Yuki Miyamoto, Hajime Hamasaki, Atsushi Sanbe, Shinji Kusakawa, Akane Nakamura, Hideki Tsumura, Masahiro Maeda, Noriko Nemoto, Katsumasa Kawahara, Tomohiro Torii, and Akito Tanoue
  • Journal Title: J. Neurosci Volume: 31 Pages: 12579-12592
  • DOI: 10.1523/JNEUROSCI.2738-11.2011
• [Presentation] Dock6 交換因子のAkt のリン酸化状態によって制御される軸索伸長の新規メカニズム(シンポジウム) (2013)
  • Author(s): 宮本 幸, 山内淳司
  • Organizer: 日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 20130900
• [Presentation] Fyn キナーゼと Arf6 交換因子cytohesin-1 による新規のミエリン形成メカニズム(シンポジウム) (2013)
  • Author(s): 山内淳司
  • Organizer: 日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 20130900
• [Presentation] 低分子量 GTP 結合蛋白質による新規のミエリン形成メカニズム (シンポジウム) (2013)
  • Author(s): 宮本 幸, 山内淳司
  • Organizer: 日本解剖学会大会
  • Place of Presentation: 香川
  • Year and Date: 20130300
• [Presentation] Novel signal transduction pathway controlling myelination(シンポジウム) (2012)
  • Author(s): 宮本幸, 山内淳司
  • Organizer: 日本神経科学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 20120900
• [Presentation] ダイナミックな形態分化を伴い, 神経軸索のミエリン化を制御するマウスRho 活性化因子 Dock7(シンポジウム) (2012)
  • Author(s): 山内淳司
  • Organizer: 日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 20120900
• [Remarks]
  • URL: http://www.ncchd.go.jp/research/nch/pharmac/index.html
• [Remarks]
  • URL: http://nch.go.jp/pharmac/