Abnormal Neurofilament Transport Caused by Targeted Disruption of Neuronal Kinesin Heavy Chain KIF5A

• Published in: The Journal of cell biology Vol. 161; no. 1; pp. 55 - 66
• Main Authors: Xia, Chun-Hong, Roberts, Elizabeth A., Her, Lu-Shiun, Liu, Xinran, Williams, David S., Cleveland, Don W., Lawrence S. B. Goldstein
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 14.04.2003; The Rockefeller University Press
• Subjects: Animals; Animals, Newborn; Antibodies; Axonal Transport - genetics; Axons; Axons - metabolism; Axons - pathology; Brain - abnormalities; Brain - growth & development; Brain - metabolism; Cellular biology; Ganglia, Spinal - abnormalities; Ganglia, Spinal - metabolism; Ganglia, Spinal - pathology; Immunohistochemistry; Integrases; Mice; Mice, Transgenic; Microtubule-Associated Proteins - deficiency; Microtubule-Associated Proteins - genetics; Motor neurons; Mutation - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nerve Fibers, Myelinated - metabolism; Nerve Fibers, Myelinated - pathology; Nerves; Neurofilament Proteins - metabolism; Neurons; Neurons, Afferent - metabolism; Neurons, Afferent - pathology; Peripheral Nerves - abnormalities; Peripheral Nerves - metabolism; Peripheral Nerves - pathology; Proteins; Sciatic nerve; Seizures - genetics; Seizures - metabolism; Sensory neurons; Spinal cord; Spinal Nerve roots; Transgenes - genetics; Viral Proteins
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200301026

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.