Analysis Tools
mortality/aging
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• 72% of mutant mice die of seizures at ~3 weeks of age, between P15 and P25
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• the remaining ~28% (8 of 29) of mutant mice survived to >3 months of age; one died at 3 months, one at 4 months, and another at 5.5 months, while the rest were sacrified at 5.5, 7, and 8 months
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growth/size/body
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• by 2-3 weeks of age, mutant mice are obviously smaller than control littermates
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• at 3 weeks of age, mutant body weight is only ~50% of control weight
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behavior/neurological
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• at 3 weeks of age, mutant mice frequently display a tremor, although their posture is relatively normal
• all mutant mice surviving to >5 months of age, develop tremors while walking
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• at 3 weeks of age, mutant mice fall off the rotarod more frequently than control mice
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• all mutant mice surviving to >5 months of age develop abnormal hindlimb posture at rest
• however, a relatively normal posture is observed until ~5 months of age
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• mutant mice surviving to >5 months of age develop a partial hindlimb paralysis
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• 72% of mutant mice die from spontaneous seizures lasting 20-30 seconds
• repetitive seizures and stress-induced seizures are also observed
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nervous system
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• 72% of mutant mice die from spontaneous seizures lasting 20-30 seconds
• repetitive seizures and stress-induced seizures are also observed
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• mutant mice surviving to >5 months of age display a striking degeneration of sensory axons within L5 lumbar dorsal roots along with numerous profiles of myelin debris
• at 3 weeks of age, mutants show a ~14% loss of sensory axon numbers within L5 dorsal roots, with a preferrential (60%) loss of large caliber sensory axons (>3 m in diameter) but no significant loss of small caliber axons
• by 5.5 months of age, mutants exhibit a ~12% loss of motor axons and a profound 36% loss of sensory axons; again, sensory and motor axon loss is most severe for large caliber axons (>4 m), and loss of ventral root axons is not as profound as that observed in the dorsal root
• at 5.5 months of age, the peak of the distribution of the diameter of large caliber axons in the ventral root shifts from 7-7.5 m in controls to 5.5-6 m in mutants
• in the dorsal roots, severe axon loss is noted in sensory axons with calibers >2 m, with complete loss of the largest sensory axons (>7 m), but no loss of small caliber sensory axons (<1.5 m)
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• at 3 weeks of age, mutant mice show a a specific deficit in the slow axonal transport of neurofilaments, as evidenced by the accumulation of NF subunits (NF-H, NF-L, and NF-M) and peripherin in the cell bodies of DRG sensory neurons
• however, no obvious changes in the amounts of NF-H, NF-M, NF-L, or peripherin are detected in the brain and sciatic nerve of mutant mice
• in addition, fast axonal transport appears to be intact, as markers of several fast axonal transport pathways (APP, Rab3, and synaptophysin) appeared unchanged in the DRG and in sciatic nerve ligation experiments
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homeostasis/metabolism
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• at 3 weeks of age, mutant mice display a striking accumulation of neurofilament (NF) subunits (NF-H, NF-L, and NF-M) and peripherin in the cell bodies of dorsal root ganglion (DRG) sensory neurons, due to a specific deficit in slow axonal transport of NFs
• neurofilament accumulation in the DRG is accompanied by a significant decrease in the number of large caliber sensory axons
• betaIII-tubulin is unchanged in younger animals, but displays behavior indicative of defective transport in some older mutant mice
• notably, accumulation of NF subunit levels in the DRG is not accompanied by obvious reductions in the sciatic nerve
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