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Published online 7 April 2003. doi:10.1083/jcb.200301026
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© The Rockefeller University Press, 0021-9525/2003/4/55 $5.00
The Journal of Cell Biology, Volume 161, Number 1, 55-66

Article

 Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A

Chun-Hong Xia1, Elizabeth A. Roberts1, Lu-Shiun Her1, Xinran Liu2, David S. Williams2, Don W. Cleveland3,4,5 and Lawrence S.B. Goldstein1

1 Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute
2 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093
3 Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093
4 Department of Medicine, University of California, San Diego, La Jolla, CA 92093
5 Neuroscience, University of California, San Diego, La Jolla, CA 92093

Address correspondence to Dr. Lawrence S.B. Goldstein, HHMI/CMM-West Room 336, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0683. Tel.: (858) 534-9702. Fax: (858) 534-9701. E-mail: lgoldstein{at}ucsd.edu

To test the hypothesis that fast anterograde molecular motor proteins power the slow axonal transport of neurofilaments (NFs), we used homologous recombination to generate mice lacking the neuronal-specific conventional kinesin heavy chain, KIF5A. Because null KIF5A mutants die immediately after birth, a synapsin-promoted Cre-recombinase transgene was used to direct inactivation of KIF5A in neurons postnatally. Three fourths of such mutant mice exhibited seizures and death at around 3 wk of age; the remaining animals survived to 3 mo or longer. In young mutant animals, fast axonal transport appeared to be intact, but NF-H, as well as NF-M and NF-L, accumulated in the cell bodies of peripheral sensory neurons accompanied by a reduction in sensory axon caliber. Older animals also developed age-dependent sensory neuron degeneration, an accumulation of NF subunits in cell bodies and a reduction in axons, loss of large caliber axons, and hind limb paralysis. These data support the hypothesis that a conventional kinesin plays a role in the microtubule-dependent slow axonal transport of at least one cargo, the NF proteins.

Key Words: slow axonal transport; neuronal kinesin heavy chain KIF5A; neurofilament; axonal caliber; DRG sensory neuron

* Abbreviations used in this paper: c-section, caesarian section; DRG, dorsal root ganglion; E, embryonic day; ES, embryonic stem; KHC, kinesin heavy chain; KLC, kinesin light chain; NF, neurofilament.


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