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

doi:10.15252/embj.201695630

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

Department of Physiology

Research output: Contribution to journal › Article › peer-review

21 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 language	English
Pages (from-to)	1227-1242
Number of pages	16
Journal	EMBO Journal
Volume	36
Issue number	9
DOIs	https://doi.org/10.15252/embj.201695630
Publication status	Published - 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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MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment. / Satake, Tomoko; Yamashita, Kazunari; Hayashi, Kenji; Miyatake, Satoko; Tamura-Nakano, Miwa; Doi, Hiroshi; Furuta, Yasuhide; Shioi, Go; Miura, Eriko; Takeo, Yukari H.; Yoshida, Kunihiro; Yahikozawa, Hiroyuki; Matsumoto, Naomichi; Yuzaki, Michisuke; Suzuki, Atsushi.

In: EMBO Journal, Vol. 36, No. 9, 02.05.2017, p. 1227-1242.

Research output: Contribution to journal › Article › peer-review

Satake, Tomoko ; Yamashita, Kazunari ; Hayashi, Kenji ; Miyatake, Satoko ; Tamura-Nakano, Miwa ; Doi, Hiroshi ; Furuta, Yasuhide ; Shioi, Go ; Miura, Eriko ; Takeo, Yukari H. ; Yoshida, Kunihiro ; Yahikozawa, Hiroyuki ; Matsumoto, Naomichi ; Yuzaki, Michisuke ; Suzuki, Atsushi. / MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment. In: EMBO Journal. 2017 ; Vol. 36, No. 9. pp. 1227-1242.

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title = "MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment",

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",

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

note = "Funding Information: The authors thank Hirokazu Hirai and Akira Iizuka for comments; Sandy Chen for her skilled technical assistance; and Aya Ogino for her assistance in the early days of the study. This research was supported by KAKENHI (to A.S.) (Grant Numbers 21116004 and 15K15069), and the Special Coordination Fund for Promoting Science and Technology ?Creation and Innovation Centers for Advanced Interdisciplinary? (to A.S.) of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, and partly supported by a grant for 2013 Strategic Research Promotion (No. IR2504) of Yokohama City University, Japan (to A.S.). The research was also partially supported by The Naito Foundation (to A.S.). Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = may,

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doi = "10.15252/embj.201695630",

language = "English",

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T1 - MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment

AU - Satake, Tomoko

AU - Yamashita, Kazunari

AU - Hayashi, Kenji

AU - Miyatake, Satoko

AU - Tamura-Nakano, Miwa

AU - Doi, Hiroshi

AU - Furuta, Yasuhide

AU - Shioi, Go

AU - Miura, Eriko

AU - Takeo, Yukari H.

AU - Yoshida, Kunihiro

AU - Yahikozawa, Hiroyuki

AU - Matsumoto, Naomichi

AU - Yuzaki, Michisuke

AU - Suzuki, Atsushi

N1 - Funding Information: The authors thank Hirokazu Hirai and Akira Iizuka for comments; Sandy Chen for her skilled technical assistance; and Aya Ogino for her assistance in the early days of the study. This research was supported by KAKENHI (to A.S.) (Grant Numbers 21116004 and 15K15069), and the Special Coordination Fund for Promoting Science and Technology ?Creation and Innovation Centers for Advanced Interdisciplinary? (to A.S.) of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, and partly supported by a grant for 2013 Strategic Research Promotion (No. IR2504) of Yokohama City University, Japan (to A.S.). The research was also partially supported by The Naito Foundation (to A.S.). Publisher Copyright: © 2017 The Authors

PY - 2017/5/2

Y1 - 2017/5/2

N2 - 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.

AB - 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.

KW - Purkinje cells

KW - axon initial segment

KW - microtubule cross-linking factor 1

KW - microtubules

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U2 - 10.15252/embj.201695630

DO - 10.15252/embj.201695630

M3 - Article

C2 - 28283581

AN - SCOPUS:85015244176

VL - 36

SP - 1227

EP - 1242

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 9

ER -

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

Abstract

Keywords

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