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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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Loss of large caliber axons in the KIF5A/KIF5Aflox; Cresynapsin mutant mice. (A) Counts of total, small (<3 μm diameter), and large (>3 μm diameter) myelinated axons in L5 ventral and dorsal roots from 3-wk-old control (n = 4) and mutant (n = 6) mice. No significant difference is observed between the number of mutant and control axons in the ventral root. There is a significant loss of dorsal root axons. *, P < 0.05 (0.045); **, P < 0.01 (0.002); t test. (B) Axon numbers of total, small (<4 μm), and large (>4 μm) myelinated axons in L5 ventral and dorsal roots from 5.5-mo-old control (1 and 2, control) and mutant (3 and 4, mutant) mice. There is a profound loss of dorsal root axons, especially large caliber axons. The loss of ventral root axons is not as profound as observed in the dorsal root. (C and D) Axonal diameters of L5 ventral root (C) and L5 dorsal root (D) from 5.5-mo-old mutant and control mice. Averaged distribution of axon diameters from the entire roots of two mutant and two control mice is shown. Note that in the ventral root (C), the peak of the distribution of the diameter of large caliber axons shifts from 7–7.5 μm in controls to 5.5–6 μm in mutants. Also note the obvious loss of large caliber axons in the dorsal root (D).
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fig5: Loss of large caliber axons in the KIF5A/KIF5Aflox; Cresynapsin mutant mice. (A) Counts of total, small (<3 μm diameter), and large (>3 μm diameter) myelinated axons in L5 ventral and dorsal roots from 3-wk-old control (n = 4) and mutant (n = 6) mice. No significant difference is observed between the number of mutant and control axons in the ventral root. There is a significant loss of dorsal root axons. *, P < 0.05 (0.045); **, P < 0.01 (0.002); t test. (B) Axon numbers of total, small (<4 μm), and large (>4 μm) myelinated axons in L5 ventral and dorsal roots from 5.5-mo-old control (1 and 2, control) and mutant (3 and 4, mutant) mice. There is a profound loss of dorsal root axons, especially large caliber axons. The loss of ventral root axons is not as profound as observed in the dorsal root. (C and D) Axonal diameters of L5 ventral root (C) and L5 dorsal root (D) from 5.5-mo-old mutant and control mice. Averaged distribution of axon diameters from the entire roots of two mutant and two control mice is shown. Note that in the ventral root (C), the peak of the distribution of the diameter of large caliber axons shifts from 7–7.5 μm in controls to 5.5–6 μm in mutants. Also note the obvious loss of large caliber axons in the dorsal root (D).

Mentions: To determine quantitatively whether the loss of KIF5A affected the survival of motor and/or sensory axons, axons of the lumbar sciatic nerve roots were counted. Comparison of the number of L5 lumbar motor axons within ventral roots of 3-wk-old KIF5A-depleted mutants and control littermates (Fig. 5 A) revealed no significant axon loss (P = 0.112), indicating that loss of KIF5A had no significant effect on the survival of motor neurons at 3 wk of age. However, sensory axon numbers within dorsal roots (Fig. 5 A) were significantly reduced in the 3-wk-old KIF5A–synapsin Cre mutant animals (∼86% of control; P = 0.045). Measurement of axonal diameter also revealed sensory loss reflected by a preferential loss of large caliber sensory axons. 60% (P = 0.002) of large caliber (>3 μm in diameter) sensory axons were lost, whereas no significant loss (P = 0.26) was observed for small caliber axons.


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)

Loss of large caliber axons in the KIF5A/KIF5Aflox; Cresynapsin mutant mice. (A) Counts of total, small (<3 μm diameter), and large (>3 μm diameter) myelinated axons in L5 ventral and dorsal roots from 3-wk-old control (n = 4) and mutant (n = 6) mice. No significant difference is observed between the number of mutant and control axons in the ventral root. There is a significant loss of dorsal root axons. *, P < 0.05 (0.045); **, P < 0.01 (0.002); t test. (B) Axon numbers of total, small (<4 μm), and large (>4 μm) myelinated axons in L5 ventral and dorsal roots from 5.5-mo-old control (1 and 2, control) and mutant (3 and 4, mutant) mice. There is a profound loss of dorsal root axons, especially large caliber axons. The loss of ventral root axons is not as profound as observed in the dorsal root. (C and D) Axonal diameters of L5 ventral root (C) and L5 dorsal root (D) from 5.5-mo-old mutant and control mice. Averaged distribution of axon diameters from the entire roots of two mutant and two control mice is shown. Note that in the ventral root (C), the peak of the distribution of the diameter of large caliber axons shifts from 7–7.5 μm in controls to 5.5–6 μm in mutants. Also note the obvious loss of large caliber axons in the dorsal root (D).
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fig5: Loss of large caliber axons in the KIF5A/KIF5Aflox; Cresynapsin mutant mice. (A) Counts of total, small (<3 μm diameter), and large (>3 μm diameter) myelinated axons in L5 ventral and dorsal roots from 3-wk-old control (n = 4) and mutant (n = 6) mice. No significant difference is observed between the number of mutant and control axons in the ventral root. There is a significant loss of dorsal root axons. *, P < 0.05 (0.045); **, P < 0.01 (0.002); t test. (B) Axon numbers of total, small (<4 μm), and large (>4 μm) myelinated axons in L5 ventral and dorsal roots from 5.5-mo-old control (1 and 2, control) and mutant (3 and 4, mutant) mice. There is a profound loss of dorsal root axons, especially large caliber axons. The loss of ventral root axons is not as profound as observed in the dorsal root. (C and D) Axonal diameters of L5 ventral root (C) and L5 dorsal root (D) from 5.5-mo-old mutant and control mice. Averaged distribution of axon diameters from the entire roots of two mutant and two control mice is shown. Note that in the ventral root (C), the peak of the distribution of the diameter of large caliber axons shifts from 7–7.5 μm in controls to 5.5–6 μm in mutants. Also note the obvious loss of large caliber axons in the dorsal root (D).
Mentions: To determine quantitatively whether the loss of KIF5A affected the survival of motor and/or sensory axons, axons of the lumbar sciatic nerve roots were counted. Comparison of the number of L5 lumbar motor axons within ventral roots of 3-wk-old KIF5A-depleted mutants and control littermates (Fig. 5 A) revealed no significant axon loss (P = 0.112), indicating that loss of KIF5A had no significant effect on the survival of motor neurons at 3 wk of age. However, sensory axon numbers within dorsal roots (Fig. 5 A) were significantly reduced in the 3-wk-old KIF5A–synapsin Cre mutant animals (∼86% of control; P = 0.045). Measurement of axonal diameter also revealed sensory loss reflected by a preferential loss of large caliber sensory axons. 60% (P = 0.002) of large caliber (>3 μm in diameter) sensory axons were lost, whereas no significant loss (P = 0.26) was observed for small caliber axons.

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