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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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Histology of KIF5A  mutant mice. (A) Lung histology of KIF5A  mutant. 7-μm lung paraffin sections from KIF5A  (KIF5A/KIF5A) and control (KIF5AWT/KIF5AWT) littermates were stained with hematoxylin and eosin. Note that the mutant lung was not well expanded. Bar, 50 μm. (B–F) Histology of KIF5A  mutant nervous tissues. Paraffin sections from spinal cord (B and C), cortex (D), hippocampus (E), and cerebellum (F) were stained with cresyl violet. Note that no obvious differences were observed between KIF5A  mutant and control littermates except that the cell bodies of the motor neurons were larger in the mutant spinal cord. Bars: (B, D, and F) 50 μm; (C) 20 μm; (E) 100 μm.
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fig2: Histology of KIF5A mutant mice. (A) Lung histology of KIF5A mutant. 7-μm lung paraffin sections from KIF5A (KIF5A/KIF5A) and control (KIF5AWT/KIF5AWT) littermates were stained with hematoxylin and eosin. Note that the mutant lung was not well expanded. Bar, 50 μm. (B–F) Histology of KIF5A mutant nervous tissues. Paraffin sections from spinal cord (B and C), cortex (D), hippocampus (E), and cerebellum (F) were stained with cresyl violet. Note that no obvious differences were observed between KIF5A mutant and control littermates except that the cell bodies of the motor neurons were larger in the mutant spinal cord. Bars: (B, D, and F) 50 μm; (C) 20 μm; (E) 100 μm.

Mentions: Because KIF5A mutant pups delivered by c-section died soon after birth and did not develop a normal breathing pattern as control littermates did, lungs from mutant and control littermates were sectioned and stained with hematoxylin-eosin. KIF5A mutant lungs did not expand as well as those of control littermates (Fig. 2 A). Thus, unexpanded lungs may be the cause of death, although the nature of the underlying mechanism is unclear. The diaphragm muscle was studied by immunostaining and electron microscopy to examine whether the neuromuscular junction region and muscle structure developed normally. No consistent abnormality was found in the mutant (unpublished data).


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)

Histology of KIF5A  mutant mice. (A) Lung histology of KIF5A  mutant. 7-μm lung paraffin sections from KIF5A  (KIF5A/KIF5A) and control (KIF5AWT/KIF5AWT) littermates were stained with hematoxylin and eosin. Note that the mutant lung was not well expanded. Bar, 50 μm. (B–F) Histology of KIF5A  mutant nervous tissues. Paraffin sections from spinal cord (B and C), cortex (D), hippocampus (E), and cerebellum (F) were stained with cresyl violet. Note that no obvious differences were observed between KIF5A  mutant and control littermates except that the cell bodies of the motor neurons were larger in the mutant spinal cord. Bars: (B, D, and F) 50 μm; (C) 20 μm; (E) 100 μm.
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Related In: Results  -  Collection

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fig2: Histology of KIF5A mutant mice. (A) Lung histology of KIF5A mutant. 7-μm lung paraffin sections from KIF5A (KIF5A/KIF5A) and control (KIF5AWT/KIF5AWT) littermates were stained with hematoxylin and eosin. Note that the mutant lung was not well expanded. Bar, 50 μm. (B–F) Histology of KIF5A mutant nervous tissues. Paraffin sections from spinal cord (B and C), cortex (D), hippocampus (E), and cerebellum (F) were stained with cresyl violet. Note that no obvious differences were observed between KIF5A mutant and control littermates except that the cell bodies of the motor neurons were larger in the mutant spinal cord. Bars: (B, D, and F) 50 μm; (C) 20 μm; (E) 100 μm.
Mentions: Because KIF5A mutant pups delivered by c-section died soon after birth and did not develop a normal breathing pattern as control littermates did, lungs from mutant and control littermates were sectioned and stained with hematoxylin-eosin. KIF5A mutant lungs did not expand as well as those of control littermates (Fig. 2 A). Thus, unexpanded lungs may be the cause of death, although the nature of the underlying mechanism is unclear. The diaphragm muscle was studied by immunostaining and electron microscopy to examine whether the neuromuscular junction region and muscle structure developed normally. No consistent abnormality was found in the mutant (unpublished data).

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