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 |
|---|---|
| Journal | EMBO Journal |
| DOIs | |
| Publication status | Accepted/In press - 2017 |
Fingerprint
Keywords
- Axon initial segment
- Microtubule cross-linking factor 1
- Microtubules
- Purkinje cells
ASJC Scopus subject areas
- Neuroscience(all)
- Molecular Biology
- Immunology and Microbiology(all)
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
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, 2017.Research output: Contribution to journal › Article
}
TY - JOUR
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
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.
KW - Axon initial segment
KW - Microtubule cross-linking factor 1
KW - Microtubules
KW - Purkinje cells
UR - http://www.scopus.com/inward/record.url?scp=85015244176&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85015244176&partnerID=8YFLogxK
U2 - 10.15252/embj.201695630
DO - 10.15252/embj.201695630
M3 - Article
C2 - 28283581
AN - SCOPUS:85015244176
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
ER -