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Age-related atrophy of motor axons in mice deficient in the mid-sized neurofilament subunit.

Elder GA, Friedrich VL, Margita A, Lazzarini RA - J. Cell Biol. (1999)

Bottom Line: The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology.By contrast, the preserved dorsal root axons of NF-M- mutant animals do not show a similar depletion of neurofilaments.These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.

ABSTRACT
Neurofilaments are central determinants of the diameter of myelinated axons. It is less clear whether neurofilaments serve other functional roles such as maintaining the structural integrity of axons over time. Here we show that an age-dependent axonal atrophy develops in the lumbar ventral roots of mice with a mutation in the mid-sized neurofilament subunit (NF-M) but not in animals with a mutation in the heavy neurofilament subunit (NF-H). Mice with mutations in both genes develop atrophy in ventral and dorsal roots as well as a hind limb paralysis with aging. The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology. In the NF-M- mutant atrophic ventral root, axons show an age-related depletion of neurofilaments and an increased ratio of microtubules/neurofilaments. By contrast, the preserved dorsal root axons of NF-M- mutant animals do not show a similar depletion of neurofilaments. Thus, the lack of an NF-M subunit renders some axons selectively vulnerable to an age-dependent atrophic process. These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

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Axonal calibers and axon number in lumbar roots of aging NF- mutant animals. (A) Diameters of all myelinated axons were measured in the L4 ventral roots of the 2-yr-old animals shown in Fig. 1. Note the marked reduction of axons >5 μm in diameter in the NF-M and NF-M/H mutants accompanied by an increase in smaller diameter fibers. (B) Diameters of myelinated axons in the dorsal roots shown in Fig. 1 were obtained by randomly sampling at least 300 myelinated axons in each root as described in Materials and Methods. Note that in contrast to the ventral roots, the distribution of axonal diameters in the NF-M– mutant is more similar to the NF-H and wild-type than to the NF-M/H. (C) Myelinated axons were counted in the  ventral lumbar roots or the L4 dorsal roots  of 2-yr-old wild-type and mutant animals. There were no statistically significant differences between the mutants and controls in any root.
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Figure 2: Axonal calibers and axon number in lumbar roots of aging NF- mutant animals. (A) Diameters of all myelinated axons were measured in the L4 ventral roots of the 2-yr-old animals shown in Fig. 1. Note the marked reduction of axons >5 μm in diameter in the NF-M and NF-M/H mutants accompanied by an increase in smaller diameter fibers. (B) Diameters of myelinated axons in the dorsal roots shown in Fig. 1 were obtained by randomly sampling at least 300 myelinated axons in each root as described in Materials and Methods. Note that in contrast to the ventral roots, the distribution of axonal diameters in the NF-M– mutant is more similar to the NF-H and wild-type than to the NF-M/H. (C) Myelinated axons were counted in the ventral lumbar roots or the L4 dorsal roots of 2-yr-old wild-type and mutant animals. There were no statistically significant differences between the mutants and controls in any root.

Mentions: Previously we found that in 4-mo-old NF-M– mutant animals axonal diameters in the ventral roots are decreased by ∼20% (Elder et al. 1998a) whereas in 4-mo-old NF-M/H– mutants axonal diameters decrease by >30% (Elder et al. 1999). To quantify the effect on axonal diameter in ventral roots of 2-yr-old NF- mutant animals we measured axonal diameters from the wild-type and mutant roots shown in Fig. 1 (see Fig. 2 and Table ). Axonal diameters were reduced by >50% in the NF-M and NF-M/H roots with axonal areas falling to <25% of control. By contrast, average axonal diameter in the 2-yr-old NF-H– mutant was only mildly decreased being within 10% of control. Similar mild effects on axonal diameter are seen in 4-mo-old NF-H– mutant roots where axonal diameters decrease by ∼18% (Elder et al. 1998b). As noted above, not all roots in 2-yr-old NF-M– mutants showed obvious atrophic changes. Interestingly, in those roots that were not obviously affected by the pathological process quantitative morphometry showed that axonal diameters were decreased by ∼20% as in young NF-M– mutant animals (data not shown).


Age-related atrophy of motor axons in mice deficient in the mid-sized neurofilament subunit.

Elder GA, Friedrich VL, Margita A, Lazzarini RA - J. Cell Biol. (1999)

Axonal calibers and axon number in lumbar roots of aging NF- mutant animals. (A) Diameters of all myelinated axons were measured in the L4 ventral roots of the 2-yr-old animals shown in Fig. 1. Note the marked reduction of axons >5 μm in diameter in the NF-M and NF-M/H mutants accompanied by an increase in smaller diameter fibers. (B) Diameters of myelinated axons in the dorsal roots shown in Fig. 1 were obtained by randomly sampling at least 300 myelinated axons in each root as described in Materials and Methods. Note that in contrast to the ventral roots, the distribution of axonal diameters in the NF-M– mutant is more similar to the NF-H and wild-type than to the NF-M/H. (C) Myelinated axons were counted in the  ventral lumbar roots or the L4 dorsal roots  of 2-yr-old wild-type and mutant animals. There were no statistically significant differences between the mutants and controls in any root.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199745&req=5

Figure 2: Axonal calibers and axon number in lumbar roots of aging NF- mutant animals. (A) Diameters of all myelinated axons were measured in the L4 ventral roots of the 2-yr-old animals shown in Fig. 1. Note the marked reduction of axons >5 μm in diameter in the NF-M and NF-M/H mutants accompanied by an increase in smaller diameter fibers. (B) Diameters of myelinated axons in the dorsal roots shown in Fig. 1 were obtained by randomly sampling at least 300 myelinated axons in each root as described in Materials and Methods. Note that in contrast to the ventral roots, the distribution of axonal diameters in the NF-M– mutant is more similar to the NF-H and wild-type than to the NF-M/H. (C) Myelinated axons were counted in the ventral lumbar roots or the L4 dorsal roots of 2-yr-old wild-type and mutant animals. There were no statistically significant differences between the mutants and controls in any root.
Mentions: Previously we found that in 4-mo-old NF-M– mutant animals axonal diameters in the ventral roots are decreased by ∼20% (Elder et al. 1998a) whereas in 4-mo-old NF-M/H– mutants axonal diameters decrease by >30% (Elder et al. 1999). To quantify the effect on axonal diameter in ventral roots of 2-yr-old NF- mutant animals we measured axonal diameters from the wild-type and mutant roots shown in Fig. 1 (see Fig. 2 and Table ). Axonal diameters were reduced by >50% in the NF-M and NF-M/H roots with axonal areas falling to <25% of control. By contrast, average axonal diameter in the 2-yr-old NF-H– mutant was only mildly decreased being within 10% of control. Similar mild effects on axonal diameter are seen in 4-mo-old NF-H– mutant roots where axonal diameters decrease by ∼18% (Elder et al. 1998b). As noted above, not all roots in 2-yr-old NF-M– mutants showed obvious atrophic changes. Interestingly, in those roots that were not obviously affected by the pathological process quantitative morphometry showed that axonal diameters were decreased by ∼20% as in young NF-M– mutant animals (data not shown).

Bottom Line: The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology.By contrast, the preserved dorsal root axons of NF-M- mutant animals do not show a similar depletion of neurofilaments.These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.

ABSTRACT
Neurofilaments are central determinants of the diameter of myelinated axons. It is less clear whether neurofilaments serve other functional roles such as maintaining the structural integrity of axons over time. Here we show that an age-dependent axonal atrophy develops in the lumbar ventral roots of mice with a mutation in the mid-sized neurofilament subunit (NF-M) but not in animals with a mutation in the heavy neurofilament subunit (NF-H). Mice with mutations in both genes develop atrophy in ventral and dorsal roots as well as a hind limb paralysis with aging. The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology. In the NF-M- mutant atrophic ventral root, axons show an age-related depletion of neurofilaments and an increased ratio of microtubules/neurofilaments. By contrast, the preserved dorsal root axons of NF-M- mutant animals do not show a similar depletion of neurofilaments. Thus, the lack of an NF-M subunit renders some axons selectively vulnerable to an age-dependent atrophic process. These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

Show MeSH
Related in: MedlinePlus