Molecular mechanisms of the formation and maintenance of NMJs

• Project/Area Number: 25460357
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: TEZUKA Tohru 東京大学, 医科学研究所, 助教 (50312319)
• Co-Investigator(Renkei-kenkyūsha): Yamanashi Yuji 東京大学, 医科学研究所, 教授 (40202387)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 神経科学 / 神経筋接合部 / シグナル伝達 / 神経筋疾患 / 神経筋シナプス / 筋無力症

Outline of Final Research Achievements

The formation and maintenance of neuromuscular junctions (NMJs), a synapse essential for motoneural control of skeletal muscle contraction, is governed by the muscle-specific receptor-tyrosine kinase MuSK. Activation of MuSK involves Agrin, Lrp4, and Dok-7. Dok-7 is an essential muscle-intrinsic activator of MuSK. On the other hand, motor neuron-derived MuSK activator Agrin binds to MuSK’s co-receptor Lrp4 and indirectly activates MuSK. In the current study, by analysis of muscle-specific Dok-7 transgenic mice lacking Lrp4, we demonstrated that Lrp4 is required for efficient activation of MuSK by Dok-7 in vivo. In addition, using recombinant adeno-associated virus vectors carrying short hairpin RNAs targeting the mouse dok-7 gene, we showed that the correct, physiological level of dok-7 gene expression is critical for the postnatal maintenance of NMJs.

Research Products

• [Journal Article] Postnatal knockdown of dok-7 gene expression in mice causes structural defects in neuromuscular synapses and myasthenic pathology (2016)
  • Author(s): Eguchi T, Tezuka T, Miyoshi S, and Yamanashi Y
  • Journal Title: Genes to Cells Volume: 印刷中 Issue: 6 Pages: 670-676
  • DOI: 10.1111/gtc.12370
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The MuSK-activator agrin has a separate role essential for postnatal maintenance of neuromuscular synapses (2014)
  • Author(s): Tohru Tezuka, Akane Inoue, Taisuke Hoshi, Scott D. Weatherbee, Robert W. Burgess, Ryo Ueta, and Yuji Yamanashi
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 111 Issue: 46 Pages: 16556-16561
  • DOI: 10.1073/pnas.1408409111
  • Peer Reviewed / Open Access
• [Journal Article] DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction (2014)
  • Author(s): Sumimasa Arimura, Takashi Okada, Tohru Tezuka, Tomoko Chiyo, Yuko Kasahara, Toshiro Yoshimura, Masakatsu Motomura, Nobuaki Yoshida, David Beeson, Shin’ichi Takeda, Yuji Yamanashi
  • Journal Title: Science Volume: 345 Issue: 6203 Pages: 1505-1508
  • DOI: 10.1126/science.1250744
  • Peer Reviewed / Open Access
• [Journal Article] Mesdc2 plays a key role in cell-surface expression of Lrp4 and postsynaptic differentiation in myotubes. (2013)
  • Author(s): Hoshi T, Tezuka T, Yokoyama K, Iemura S-I, Natsume T, and Yamanashi Y
  • Journal Title: FEBS Lett. Volume: 587 Issue: 23 Pages: 3749-3754
  • DOI: 10.1016/j.febslet.2013.10.001
  • Peer Reviewed
• [Journal Article] Protocadherin 17 regulates presynaptic assembly in topographic corticobasal Ganglia circuits (2013)
  • Author(s): Hoshina N, Tanimura A, Yamasaki M, Inoue T, Fukabori R, Kuroda T, Yokoyama K, Tezuka T, Sagara H, Hirano S, Kiyonari H, Takada M, Kobayashi K, Watanabe M, Kano M, Nakazawa T, Yamamoto T
  • Journal Title: Neuron Volume: 78(5) Issue: 5 Pages: 839-854
  • DOI: 10.1016/j.neuron.2013.03.031
  • Peer Reviewed
• [Journal Article] An adaptor protein complex of FRS2beta and CIN85/CD2AP provides a novel mechanism for ErbB2/HER2 protein downregulation (2013)
  • Author(s): 後藤 典子
  • Journal Title: Cancer Sci Volume: 104 Issue: 3 Pages: 345-352
  • DOI: 10.1111/cas.12086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 神経筋接合部の出生後の維持におけるAgrinの新たな役割 (2015)
  • Author(s): 手塚徹、井上茜、星太輔、Weatherbee SD、Burgess RW、植田亮、山梨裕司
  • Organizer: 日本筋学会
  • Place of Presentation: 国立研究開発法人国立精神・神経医療研究センター（東京都小平市）
  • Year and Date: 2015-08-08
• [Remarks] 発表論文解説（東京大学医科学研究所）
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/research/papers/post_58.php
• [Remarks] 主な研究成果（東京大学医科学研究所腫瘍抑制分野）
  • URL: http://www.ims.u-tokyo.ac.jp/genetics/html/Research.html