MTCL1 plays an essential role to maintain axon initial segment

2016 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

分子細胞生物学