MTCL1 plays an essential role to maintain axon initial segment

• Project/Area Number: 15K15069
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Yokohama City University
• Principal Investigator: SUZUKI Atsushi 横浜市立大学, 生命医科学研究科, 准教授 (00264606)
• Co-Investigator(Renkei-kenkyūsha): SATAKE Tomoko 横浜市立大学, 生命医科学研究科, 特任助教 (20635130) ; MIYATAKE Satoko 横浜市立大学, 附属病院, 講師 (50637890)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 微小管 / 軸索起始部 / 架橋 / MTCL1 / 脊髄小脳変性症 / アンキリン / プルキンエ細胞 / 微小管安定化 / 運動失調 / 小脳 / AIS

Outline of Final Research Achievements

The axon initial segment (AIS) is a specialized domain essential for neuronal function, the formation of which begins with localization of an Ankyrin-G (AnkG) scaffold. However, the mechanism directing and maintaining AnkG localization is largely unknown. In this study, we demonstrate that in vivo knockdown of MTCL1 in cerebellar Purkinje cells causes loss of axonal polarity coupled with AnkG mislocalization. MTCL1 lacking MT-stabilizing activity failed to restore these defects. Interestingly, during postnatal AIS development, colocalization of MTCL1 with these stable MT bundles was transiently observed in the axon hillock and proximal axon. These results indicate that MTCL1-mediated formation of stable MT bundles is crucial for AnkG localization. We also demonstrate that Mtcl1-gene disruption results in abnormal motor coordination with Purkinje cell degeneration, and provide evidence suggesting possible involvement of MTCL1 dysfunction in the pathogenesis of spinocerebellar ataxia.

Research Products

• [Journal Article] MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment. (2017)
  • Author(s): Satake T, Yamashita K, Hayashi K, Miyatake S, Tamura-Nakano M, Doi H, Furuta Y, Shioi G, Miura E, Takeo YH, Yoshida K, Yahikozawa H, Matsumoto N, Yuzaki M, Suzuki A.
  • Journal Title: EMBOJ Volume: 36 Issue: 9 Pages: 1227-1242
  • DOI: 10.15252/embj.201695630
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Role of MTCL1, a microtubule crosslinking and stabilizing protein, in the formation of axon initial segment (2016)
  • Author(s): Tomoko Satake, Atsushi Suzuki
  • Organizer: 米国細胞生物学会
  • Place of Presentation: 米国 サンフランシスコ Moscone center
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] 軸索起始部AISの形成における微小管架橋/安定化因子MTCL1の役割 (2016)
  • Author(s): 佐竹智子、鈴木厚
  • Organizer: 第39回 日本分子生物学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] 微小管架橋/安定化因子MTCL1は、軸索起始部AIS形成に必須である (2016)
  • Author(s): 佐竹智子、鈴木厚
  • Organizer: 第68回 日本細胞生物学会
  • Place of Presentation: 京都テルサ：京都府民総合交流プラザ（京都府京都市）
  • Year and Date: 2016-06-15
• [Presentation] Organization of dynamic microtubules by a microtubule crosslinking factor, MTCL1 (2015)
  • Author(s): 鈴木 厚
  • Organizer: 第67回 日本細胞生物学会
  • Place of Presentation: 東京都江戸川区 タワーホール船堀
  • Year and Date: 2015-06-30
• [Presentation] Molecular basis of MTCL1 functions in regulating MT organization. (2015)
  • Author(s): Mohammad A Kader, 佐竹 智子、鈴木 厚
  • Organizer: 第67回 日本細胞生物学会
  • Place of Presentation: 東京都江戸川区 タワーホール船堀
  • Year and Date: 2015-06-30
• [Remarks] 横浜市立大学 分子細胞医科学研究室 鈴木グループ HP
  • URL: http://www.tsurumi.yokohama-cu.ac.jp/mcbl/suzuki/index.html
• [Remarks] 運動失調症が引き起こされる新たなメカニズムを発見しました！
  • URL: http://www.yokohama-cu.ac.jp/res_pro/news/10170324.html