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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

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