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EMBO J. 2017 May 2;36(9):1227-1242. doi: 10.15252/embj.201695630. Epub 2017 Mar 10.

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

Author information

1
Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, Tsurumi-ku Yokohama, Japan.
2
Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Kanazawa-ku Yokohama, Japan.
3
Department of Human Genetics, Yokohama City University Graduate School of Medical Science, Kanazawa-ku Yokohama, Japan.
4
Communal Laboratory, Research Institute, National Center for Global Health and Medicine, Toyama Shinjuku-ku Tokyo, Japan.
5
Department of Neurology, Yokohama City University Graduate School of Medical Science, Kanazawa-ku Yokohama, Japan.
6
Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Chuou-ku Kobe, Japan.
7
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Chuou-ku Kobe, Japan.
8
Department of Physiology, School of Medicine, Keio University, Shinjuku-ku Tokyo, Japan.
9
Division of Neurogenetics, Department of Brain Disease Research, Shinshu University School of Medicine, Asahi Matsumoto, Japan.
10
Department of Neurology, Nagano Red Cross Hospital, Wakasato Nagano, Japan.
11
Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, Tsurumi-ku Yokohama, Japan abell@tsurumi.yokohama-cu.ac.jp.

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.

KEYWORDS:

Purkinje cells; axon initial segment; microtubule cross‐linking factor 1; microtubules

PMID:
28283581
PMCID:
PMC5412768
DOI:
10.15252/embj.201695630
[Indexed for MEDLINE]
Free PMC Article

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