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

研究成果: Article

15 引用 (Scopus)

抄録

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.

元の言語English
ジャーナルEMBO Journal
DOI
出版物ステータスAccepted/In press - 2017

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Ankyrins
Purkinje Cells
Microtubules
Neurons
Spinocerebellar Ataxias
Scaffolds
Genes
Axons
Defects
Maintenance
Axon Initial Segment

ASJC Scopus subject areas

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

これを引用

Satake, T., Yamashita, K., Hayashi, K., Miyatake, S., Tamura-Nakano, M., Doi, H., ... Suzuki, A. (受理済み/印刷中). MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment. EMBO Journal. https://doi.org/10.15252/embj.201695630

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.

:: EMBO Journal, 2017.

研究成果: Article

Satake, T, Yamashita, K, Hayashi, K, Miyatake, S, Tamura-Nakano, M, Doi, H, Furuta, Y, Shioi, G, Miura, E, Takeo, YH, Yoshida, K, Yahikozawa, H, Matsumoto, N, Yuzaki, M & Suzuki, A 2017, 'MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment', EMBO Journal. https://doi.org/10.15252/embj.201695630
Satake T, Yamashita K, Hayashi K, Miyatake S, Tamura-Nakano M, Doi H その他. MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment. EMBO Journal. 2017. https://doi.org/10.15252/embj.201695630
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. :: EMBO Journal. 2017.
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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.",
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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

PY - 2017

Y1 - 2017

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.

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KW - Microtubule cross-linking factor 1

KW - Microtubules

KW - Purkinje cells

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