Roles of MEGF10 in the pathomechanisms of myopathy

Research Project

Project/Area Number	17K16132
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Neurology
Research Institution	Yokohama City University
Principal Investigator	Mitsuhashi Satomi 横浜市立大学, 医学部, 助教 (40466222)
Project Period (FY)	2017-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords	筋疾患 / 骨格筋再生 / トランスクリプトーム / 筋細胞分化 / 疾患生物学
Outline of Final Research Achievements	Mutations in cell membrane protein MEGF10 cause early onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD), a rare congenital muscle disease, but the pathogenic mechanisms remain largely unknown. We demonstrate that loss of Megf10, as well as overexpression of the pathogenic human C774R mutation, leads to impaired proliferation and migration of C2C12 cells. Cell proliferation and migration are known to be regulated by the Notch receptor, which plays an essential role in myogenesis. Reciprocal co-immunoprecipitation studies show that Megf10 and Notch1 interact via their respective intracellular domains. These interactions are impaired by the pathogenic C774R mutation. Megf10 regulation of myoblast function appears to be mediated at least in part via interactions with key components of the Notch signaling pathway, and defects in these interactions may contribute to the pathogenesis of EMARDD.
Academic Significance and Societal Importance of the Research Achievements	本研究により、MEGF10の骨格筋におけるシグナリング分子を同定することで、MEGF10の変異によっておこる希少遺伝性筋疾患の分子病態メカニズムを示したことから、今後の治療法開発へも繋がることが期待される。また、骨格筋再生の基礎メカニズムおけるMEGF10の役割についても、示唆的な結果を示すことができたと考えている。