Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice

Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice

The nerve axon is a good model system for studying the molecular mechanism of organelle transport in cells. Recently, the new kinesin superfamily proteins (KIFs) have been identified as candidate motor proteins involved in organelle transport. Among them KIF1A, a murine homologue of unc-104 gene of...

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Main Authors: Yonekawa, Yoshiaki, Harada, Akihiro, Okada, Yasushi, Funakoshi, Takeshi, Kanai, Yoshimitsu, Takei, Yosuke, Terada, Sumio, Noda, Tetsuo, Hirokawa, Nobutaka
Format: Online
Language:English
Published: The Rockefeller University Press 1998
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148442/
id pubmed-2148442
recordtype oai_dc
spelling pubmed-21484422008-05-01 Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice Yonekawa, Yoshiaki Harada, Akihiro Okada, Yasushi Funakoshi, Takeshi Kanai, Yoshimitsu Takei, Yosuke Terada, Sumio Noda, Tetsuo Hirokawa, Nobutaka Articles The nerve axon is a good model system for studying the molecular mechanism of organelle transport in cells. Recently, the new kinesin superfamily proteins (KIFs) have been identified as candidate motor proteins involved in organelle transport. Among them KIF1A, a murine homologue of unc-104 gene of Caenorhabditis elegans, is a unique monomeric neuron– specific microtubule plus end–directed motor and has been proposed as a transporter of synaptic vesicle precursors (Okada, Y., H. Yamazaki, Y. Sekine-Aizawa, and N. Hirokawa. 1995. Cell. 81:769–780). To elucidate the function of KIF1A in vivo, we disrupted the KIF1A gene in mice. KIF1A mutants died mostly within a day after birth showing motor and sensory disturbances. In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and significant decrease. Consequently, synaptic vesicle density decreased dramatically, and clusters of clear small vesicles accumulated in the cell bodies. Furthermore, marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons. The neuronal death in cultures was blocked by coculture with wild-type neurons or exposure to a low concentration of glutamate. These results in cultures suggested that the mutant neurons might not sufficiently receive afferent stimulation, such as neuronal contacts or neurotransmission, resulting in cell death. Thus, our results demonstrate that KIF1A transports a synaptic vesicle precursor and that KIF1A-mediated axonal transport plays a critical role in viability, maintenance, and function of neurons, particularly mature neurons. The Rockefeller University Press 1998-04-20 /pmc/articles/PMC2148442/ /pubmed/9548721 Text en This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Yonekawa, Yoshiaki
Harada, Akihiro
Okada, Yasushi
Funakoshi, Takeshi
Kanai, Yoshimitsu
Takei, Yosuke
Terada, Sumio
Noda, Tetsuo
Hirokawa, Nobutaka
spellingShingle Yonekawa, Yoshiaki
Harada, Akihiro
Okada, Yasushi
Funakoshi, Takeshi
Kanai, Yoshimitsu
Takei, Yosuke
Terada, Sumio
Noda, Tetsuo
Hirokawa, Nobutaka
Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice
author_facet Yonekawa, Yoshiaki
Harada, Akihiro
Okada, Yasushi
Funakoshi, Takeshi
Kanai, Yoshimitsu
Takei, Yosuke
Terada, Sumio
Noda, Tetsuo
Hirokawa, Nobutaka
author_sort Yonekawa, Yoshiaki
title Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice
title_short Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice
title_full Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice
title_fullStr Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice
title_full_unstemmed Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice
title_sort defect in synaptic vesicle precursor transport and neuronal cell death in kif1a motor protein–deficient mice
description The nerve axon is a good model system for studying the molecular mechanism of organelle transport in cells. Recently, the new kinesin superfamily proteins (KIFs) have been identified as candidate motor proteins involved in organelle transport. Among them KIF1A, a murine homologue of unc-104 gene of Caenorhabditis elegans, is a unique monomeric neuron– specific microtubule plus end–directed motor and has been proposed as a transporter of synaptic vesicle precursors (Okada, Y., H. Yamazaki, Y. Sekine-Aizawa, and N. Hirokawa. 1995. Cell. 81:769–780). To elucidate the function of KIF1A in vivo, we disrupted the KIF1A gene in mice. KIF1A mutants died mostly within a day after birth showing motor and sensory disturbances. In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and significant decrease. Consequently, synaptic vesicle density decreased dramatically, and clusters of clear small vesicles accumulated in the cell bodies. Furthermore, marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons. The neuronal death in cultures was blocked by coculture with wild-type neurons or exposure to a low concentration of glutamate. These results in cultures suggested that the mutant neurons might not sufficiently receive afferent stimulation, such as neuronal contacts or neurotransmission, resulting in cell death. Thus, our results demonstrate that KIF1A transports a synaptic vesicle precursor and that KIF1A-mediated axonal transport plays a critical role in viability, maintenance, and function of neurons, particularly mature neurons.
publisher The Rockefeller University Press
publishDate 1998
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148442/
_version_ 1611423610733330432

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