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

Author:

Xia Chun-Hong1,Roberts Elizabeth A.1,Her Lu-Shiun1,Liu Xinran2,Williams David S.2,Cleveland Don W.345,Goldstein Lawrence S.B.1

Affiliation:

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

Abstract

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.

Publisher

Rockefeller University Press

Subject

Cell Biology

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