Molecular signaling in neuromuscular synaptogenesis and myasthenia

2014 Fiscal Year Final Research Report

• Project/Area Number: 23249013
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: YAMANASHI Yuji 東京大学, 医科学研究所, 教授 (40202387)
• Co-Investigator(Kenkyū-buntansha): TEZUKA Tohru 東京大学, 医科学研究所, 助教 (50312319)
• Co-Investigator(Renkei-kenkyūsha): NUREKI Osamu 東京大学, 理学系研究科, 教授 (10272460) ; NATSUME Tohru 産業技術総合研究所, 創薬分子プロファイリング研究センター, センター長 (00357683) ; TAKEDA Shin'ICHI 国立精神, 神経医療研究センター・神経研究所, 部長 (90171644) ; MOTOMURA Masakatsu 長崎総合科学大学, 工学部, 教授 (70244093)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Keywords: 細胞内シグナル伝達

Outline of Final Research Achievements

We previously revealed that the cytoplasmic adaptor-like protein Dok-7 activates muscle-specific receptor tyrosine kinase MuSK, which is required for neuromuscular synaptogenesis and maintenance. To understand molecular signaling involved in neuromuscular synaptogenesis and myasthenia, we not only studied Dok-7 and MuSK-mediated signaling but also other signaling pathways in skeletal muscle. Our findings revealed that the chaperon protein Mesdc2 plays an important role in cell-surface expression of MuSK’s co-receptor Lrp4, which is essential for NMJ formation and maintenance. Also, we found that the MuSK activator agrin has a separate role in postnatal maintenance of NMJ. Furthermore, we developed an adeno-associated viral vector (AAV-D7), which expresses Dok-7, and showed that AAV-D7 treatment enlarged NMJs and restored motor activities of DOK7 myasthenia model mice, resulting in enhancement of their survival.

Free Research Field

分子生物学