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 thatin vivoknockdown 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 thatMtcl1gene 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.
authors.affiliation: Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, Tsurumi-ku Yokohama, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Satake
authors.affiliation: Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Kanazawa-ku Yokohama, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Kanazawa-ku Yokohama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medical Science, Kanazawa-ku Yokohama, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Communal Laboratory, Research Institute, National Center for Global Health and Medicine, Toyama Shinjuku-ku Tokyo, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Tamura-Nakano
authors.affiliation: Department of Neurology, Yokohama City University Graduate School of Medical Science, Kanazawa-ku Yokohama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.affiliation: Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Chuou-ku Kobe, Japan.|Genetic Engineering Team, RIKEN Center for Life Science Technologies, Chuou-ku Kobe, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Furuta
authors.affiliation: Genetic Engineering Team, RIKEN Center for Life Science Technologies, Chuou-ku Kobe, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Shioi
authors.affiliation: Department of Physiology, School of Medicine, Keio University, Shinjuku-ku Tokyo, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Miura
authors.affiliation: Department of Physiology, School of Medicine, Keio University, Shinjuku-ku Tokyo, Japan.
authors.forename: Yukari H
authors.initials: YH
authors.lastname: Takeo
authors.affiliation: Division of Neurogenetics, Department of Brain Disease Research, Shinshu University School of Medicine, Asahi Matsumoto, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Neurology, Nagano Red Cross Hospital, Wakasato Nagano, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yahikozawa
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medical Science, Kanazawa-ku Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Physiology, School of Medicine, Keio University, Shinjuku-ku Tokyo, Japan.
authors.forename: Michisuke
authors.initials: M
authors.lastname: Yuzaki
authors.affiliation: Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, Tsurumi-ku Yokohama, Japan abell@tsurumi.yokohama-cu.ac.jp.
authors.forename: Atsushi
authors.identifier: 0000-0002-3026-3026
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000071040:Axon Initial Segment / Q000502:physiology*; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D000068079:Motor Disorders; D011689:Purkinje Cells / Q000166:cytology* / Q000502:physiology*
chemical_list: C000621135:MTCL1 protein, mouse; D008869:Microtubule-Associated Proteins
keywords: Purkinje cells; axon initial segment; microtubule cross‐linking factor 1; microtubules