Pathogenesis of a neurodevelopmental disorder caused by human beta3 tubulin gene mutations

• Project/Area Number: 26430080
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Minoura Itsushi 国立研究開発法人理化学研究所, 脳科学総合研究センター, 客員研究員 (70373371)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: チューブリン / 外眼筋線維症 / 微小管 / ダイナミクス / キネシン / クライオ電子顕微鏡 / 外眼筋繊維症 / 神経軸索形成 / レスキュー

Outline of Final Research Achievements

Mutation at R262 amino acid residue of human beta3 tubulin impairs axon growth which leads to congenital fibrosis of extraocular muscles type 3. A model of the axon growth defects was constructed, which was rescued by a mutation at L12 loop of KIF21A or of KIF5B. These mutations recover the binding of these kinesin molecules to microtubules composed of beta-3 tubulin. These kinesins may control the dynamics of beta-3-tubulin rich microtubules which play essential roles in neuronal development. Our result suggests that these kinesin control the dynamics of such microtubules and these microtubues are important for axon growth and steering during brain morphogenesis.

Research Products

• [Journal Article] Towards an understanding of the isotype-specific functions of tubulin in neurons: Technical advances in tubulin expression and purification (2017)
  • Author(s): Itsushi Minoura
  • Journal Title: Neuroscience Research Volume: 印刷中 Pages: 1-8
  • DOI: 10.1016/j.neures.2017.04.002
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reversal of axonal growth defects in an extraocular fibrosis model by engineering the kinesin-microtubule interface. (2016)
  • Author(s): Minoura I, Takazaki H, Ayukawa R, Saruta C, Hachikubo Y, Uchimura S, Hida T, Kamiguchi H, Shimogori T, Muto E
  • Journal Title: Nature communications Volume: 7 Issue: 1 Pages: 10058-10058
  • DOI: 10.1038/ncomms10058
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A flipped ion pair at the dynein-microtubule interface is critical for dynein motility and ATPase activation (2015)
  • Author(s): Uchimura, S., Fujii, T., Takazaki, H., Ayukawa, R., Nishikawa, Y., Minoura, I., Hachikubo, Y., Kurisu, G., Sutoh, K., Kon, T., Namba, K., Muto, E.
  • Journal Title: J. Cell Biol. Volume: 208 Issue: 2 Pages: 211-222
  • DOI: 10.1083/jcb.201407039
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Reversal of axonal growth defects in an extraocular fibrosis model by engineering the kinesin-microtubule interface (2016)
  • Author(s): Itsushi Minoura
  • Organizer: CSH-Asia Conference: Development, Function & Disease of Neural Circuits
  • Place of Presentation: Shuzou, China
  • Year and Date: 2016-05-17
  • Int'l Joint Research
• [Presentation] A Mechanical Switch from Diffusion to Directional Motion Activates ATPase in Dynein Motor (2015)
  • Author(s): S. Uchimura, T. Fujii, H. Takazaki, R. Ayukawa, Y. Nishikawa, Itsushi Minoura, Y. Hachikubo, G. Kurisu, K. Sutoh, T. Kon, K. Namba, E. Muto
  • Organizer: Biophysical Society 59th Annual Meeting
  • Place of Presentation: Baltimore, USA
  • Year and Date: 2015-02-07 – 2015-02-11
• [Remarks] 先天性外眼筋繊維症に伴う神経発達異常の仕組みを解明
  • URL: http://www.riken.jp/pr/press/2016/20160118_2/