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

doi:info:doi/10.1083/jcb.141.2.431

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タイトル	Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein-deficient Mice
著者	Yonekawa, Yoshiaki Yonekawa, Yoshiaki
	Harada, Akihiro Harada, Akihiro
	Okada, Yasushi Okada, Yasushi
	Funakoshi, Takeshi Funakoshi, Takeshi
	Kanai, Yoshimitsu Kanai, Yoshimitsu
	Takei, Yosuke Takei, Yosuke
	Terada, Sumio Terada, Sumio
	Noda, Tetsuo Noda, Tetsuo
	Hirokawa, Nobutaka Hirokawa, Nobutaka
抄録	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 neuronspecific 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.
公開者	The Rockefeller University Press
掲載誌名	Journal of Cell Biology
巻	141
号	2
開始ページ	431
終了ページ	441
刊行年月	1998-04-20
ISSN	00219525
NCID	AA00694812
DOI	info:doi/10.1083/jcb.141.2.431
URL	http://hdl.handle.net/11094/23080
言語	英語

著者版フラグ	publisher
NII資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
dcmi資源タイプ	text
DCTERMS.bibliographicCitation	Journal of Cell Biology.141(2) P.431-P.441
DC.title	Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein-deficient Mice
DC.creator	Yonekawa, Yoshiaki
	Harada, Akihiro
	Okada, Yasushi
	Funakoshi, Takeshi
	Kanai, Yoshimitsu
	Takei, Yosuke
	Terada, Sumio
	Noda, Tetsuo
	Hirokawa, Nobutaka
DC.publisher	The Rockefeller University Press
DC.language" scheme="DCTERMS.RFC1766	英語
DCTERMS.issued" scheme="DCTERMS.W3CDTF	1998-04-20
DC.identifier	info:doi/10.1083/jcb.141.2.431
DC.identifier" scheme="DCTERMS.URI	http://hdl.handle.net/11094/23080
DCTERMS.abstract	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 neuronspecific 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.
citation_title	Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein-deficient Mice
citation_author	Yonekawa, Yoshiaki
	Harada, Akihiro
	Okada, Yasushi
	Funakoshi, Takeshi
	Kanai, Yoshimitsu
	Takei, Yosuke
	Terada, Sumio
	Noda, Tetsuo
	Hirokawa, Nobutaka
citation_publisher	The Rockefeller University Press
citation_language	英語
citation_date	1998-04-20
citation_journal_title	Journal of Cell Biology
citation_volume	141
citation_issue	2
citation_firstpage	431
citation_lastpage	441
citation_issn	00219525
citation_doi	info:doi/10.1083/jcb.141.2.431
citation_public_url	http://hdl.handle.net/11094/23080

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