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

Xia CH, Roberts EA, Her LS, Liu X, Williams DS, Cleveland DW, Goldstein LS - J. Cell Biol. (2003)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093-0683, USA.

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 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.

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Sensory axon degeneration in KIF5A/KIF5Aflox; Cresynapsin mutant mice. (A) Ventral roots of 3-wk-old and 5.5-mo-old mutant mice. Note the lack of degeneration. Bar, 50 μm. (B) Dorsal roots of 3-wk-old and 5.5-mo-old mutant mice. Note the lack of degeneration in 3-wk sensory axons, but in the 5.5-mo-old mutant, there are large numbers of degenerating axons (arrowheads) and a striking decrease of large caliber axons. Bar, 20 μm.
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fig4: Sensory axon degeneration in KIF5A/KIF5Aflox; Cresynapsin mutant mice. (A) Ventral roots of 3-wk-old and 5.5-mo-old mutant mice. Note the lack of degeneration. Bar, 50 μm. (B) Dorsal roots of 3-wk-old and 5.5-mo-old mutant mice. Note the lack of degeneration in 3-wk sensory axons, but in the 5.5-mo-old mutant, there are large numbers of degenerating axons (arrowheads) and a striking decrease of large caliber axons. Bar, 20 μm.

Mentions: In spite of the obvious neuromuscular phenotype, no obvious morphological abnormality in spinal cord or DRG was observed in KIF5A/KIF5Aflox; Cresynapsin mutants at either 3 wk or 7.5 mo of age (unpublished data). Examination of thin sections of ventral roots (Fig. 4 A) did not detect any obvious abnormality in 3-wk-, 5.5-mo-, or 7.5-mo-old mutant mice. Whereas no degeneration was detected in sensory axons of the dorsal roots from 3-wk-old animals (Fig. 4 B), four older mutant mice (two 5.5- and two 7.5-mo-old mice) showed striking degeneration of axons (Fig. 4 B), with numerous profiles of myelin debris (typical of Wallerian degeneration). This phenotype was not observed in the control littermates (KIF5Aflox/KIF5AWT or KIF5A/KIF5Aflox). These data are consistent with an age-dependent onset of abnormal hind limb posture after loss of KIF5A.


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

Xia CH, Roberts EA, Her LS, Liu X, Williams DS, Cleveland DW, Goldstein LS - J. Cell Biol. (2003)

Sensory axon degeneration in KIF5A/KIF5Aflox; Cresynapsin mutant mice. (A) Ventral roots of 3-wk-old and 5.5-mo-old mutant mice. Note the lack of degeneration. Bar, 50 μm. (B) Dorsal roots of 3-wk-old and 5.5-mo-old mutant mice. Note the lack of degeneration in 3-wk sensory axons, but in the 5.5-mo-old mutant, there are large numbers of degenerating axons (arrowheads) and a striking decrease of large caliber axons. Bar, 20 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172877&req=5

fig4: Sensory axon degeneration in KIF5A/KIF5Aflox; Cresynapsin mutant mice. (A) Ventral roots of 3-wk-old and 5.5-mo-old mutant mice. Note the lack of degeneration. Bar, 50 μm. (B) Dorsal roots of 3-wk-old and 5.5-mo-old mutant mice. Note the lack of degeneration in 3-wk sensory axons, but in the 5.5-mo-old mutant, there are large numbers of degenerating axons (arrowheads) and a striking decrease of large caliber axons. Bar, 20 μm.
Mentions: In spite of the obvious neuromuscular phenotype, no obvious morphological abnormality in spinal cord or DRG was observed in KIF5A/KIF5Aflox; Cresynapsin mutants at either 3 wk or 7.5 mo of age (unpublished data). Examination of thin sections of ventral roots (Fig. 4 A) did not detect any obvious abnormality in 3-wk-, 5.5-mo-, or 7.5-mo-old mutant mice. Whereas no degeneration was detected in sensory axons of the dorsal roots from 3-wk-old animals (Fig. 4 B), four older mutant mice (two 5.5- and two 7.5-mo-old mice) showed striking degeneration of axons (Fig. 4 B), with numerous profiles of myelin debris (typical of Wallerian degeneration). This phenotype was not observed in the control littermates (KIF5Aflox/KIF5AWT or KIF5A/KIF5Aflox). These data are consistent with an age-dependent onset of abnormal hind limb posture after loss of KIF5A.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093-0683, USA.

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 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.

Show MeSH
Related in: MedlinePlus