MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment

Tomoko Satake, Kazunari Yamashita, Kenji Hayashi, Satoko Miyatake, Miwa Tamura-Nakano, Hiroshi Doi, Yasuhide Furuta, Go Shioi, Eriko Miura, Yukari H. Takeo, Kunihiro Yoshida, Hiroyuki Yahikozawa, Naomichi Matsumoto, Michisuke Yuzaki, Atsushi Suzuki

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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 microtubule cross-linking factor 1 (MTCL1) in cerebellar Purkinje cells causes loss of axonal polarity coupled with AnkG mislocalization. MTCL1 lacking MT-stabilizing activity failed to restore these defects, and stable MT bundles spanning the AIS were disorganized in knockdown cells. Interestingly, during early postnatal development, colocalization of MTCL1 with these stable MT bundles was observed prominently in the axon hillock and proximal axon. These results indicate that MTCL1-mediated formation of stable MT bundles is crucial for maintenance of 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.

Original languageEnglish
Pages (from-to)1227-1242
Number of pages16
JournalEMBO Journal
Volume36
Issue number9
DOIs
Publication statusPublished - 2017 May 2

Keywords

  • Purkinje cells
  • axon initial segment
  • microtubule cross-linking factor 1
  • microtubules

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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