Loss of α-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function

Koji Ikegami; Robb L Heier; Midori Taruishi; Hiroshi Takagi; Masahiro Mukai; Shuichi Shimma; Shu Taira; Ken Hatanaka; Nobuhiro Morone; Ikuko Yao; Patrick K Campbell; Shigeki Yuasa; Carsten Janke; Grant R MacGregor; Mitsutoshi Setou

doi:10.1073/pnas.0611547104

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Loss of α-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function

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Loss of α-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function

Koji Ikegami, Robb L Heier, Midori Taruishi, Hiroshi Takagi, Masahiro Mukai, Shuichi Shimma, Shu Taira, Ken Hatanaka, Nobuhiro Morone, Ikuko Yao, …

Proceedings of the National Academy of Sciences - PNAS, Vol.104(9), pp.3213-3218

02/27/2007

DOI: 10.1073/pnas.0611547104

PMCID: PMC1802010

PMID: 17360631

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Abstract

Microtubules function as molecular tracks along which motor proteins transport a variety of cargo to discrete destinations within the cell. The carboxyl termini of α- and β-tubulin can undergo different posttranslational modifications, including polyglutamylation, which is particularly abundant within the mammalian nervous system. Thus, this modification could serve as a molecular “traffic sign” for motor proteins in neuronal cells. To investigate whether polyglutamylated α-tubulin could perform this function, we analyzed ROSA22 mice that lack functional PGs1, a subunit of α-tubulin-selective polyglutamylase. In wild-type mice, polyglutamylated α-tubulin is abundant in both axonal and dendritic neurites. ROSA22 mutants display a striking loss of polyglutamylated α-tubulin within neurons, including their neurites, which is associated with decreased binding affinity of certain structural microtubule-associated proteins and motor proteins, including kinesins, to microtubules purified from ROSA22-mutant brain. Of the kinesins examined, KIF1A, a subfamily of kinesin-3, was less abundant in neurites from ROSA22 mutants in vitro and in vivo, whereas the distribution of KIF3A (kinesin-2) and KIF5 (kinesin-1) appeared unaltered. The density of synaptic vesicles, a cargo of KIF1A, was decreased in synaptic terminals in the CA1 region of hippocampus in ROSA22 mutants. Consistent with this finding, ROSA22 mutants displayed more rapid depletion of synaptic vesicles than wild-type littermates after high-frequency stimulation. These data provide evidence for a role of polyglutamylation of α-tubulin in vivo, as a molecular traffic sign for targeting of KIF1 kinesin required for continuous synaptic transmission.

Biological Sciences

tyrosination

microtubules

synaptic vesicles

trafficking

kinesin

Details

Title: Subtitle: Loss of α-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function
Creators: Koji Ikegami - Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan
Robb L Heier - Department of Developmental and Cell Biology, Developmental Biology Center, and Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697-3940
Midori Taruishi - Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan
Hiroshi Takagi - Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan
Masahiro Mukai - Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan
Shuichi Shimma - National Institute for Physiological Sciences, Okazaki, Aichi 444-8787, Japan
Shu Taira - Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan
Ken Hatanaka - Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan
Nobuhiro Morone - Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan; and
Ikuko Yao - Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan
Patrick K Campbell - Department of Developmental and Cell Biology, Developmental Biology Center, and Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697-3940
Shigeki Yuasa - Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan; and
Carsten Janke - Centre de Rechérches en Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, 34293 Montpellier, France
Grant R MacGregor - Department of Developmental and Cell Biology, Developmental Biology Center, and Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697-3940
Mitsutoshi Setou - Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.104(9), pp.3213-3218
DOI: 10.1073/pnas.0611547104
PMID: 17360631
PMCID: PMC1802010
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 02/27/2007
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984068362202771

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