title: Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093-0683, USA.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Xia
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Roberts
authors.forename: Lu-Shiun
authors.initials: LS
authors.lastname: Her
authors.forename: Xinran
authors.initials: X
authors.lastname: Liu
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001370:Axonal Transport / Q000235:genetics*; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D019426:Integrases; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology; D010525:Peripheral Nerves / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D012640:Seizures / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D014764:Viral Proteins
chemical_list: C411575:KIFC5 protein, mouse; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases