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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 morphology in dorsal and ventral roots of old NF- mutant animals. Light microscopy of toluidine blue–stained cross sections of L4 dorsal (A, C, E, and G) or L4 ventral (B, D, F, and H) roots from 2-yr-old wild-type (A and B), NF-M– mutant (C and D), NF-H– mutant (E and F), or NF-M/H– mutant (G and H) mice. Insets show cross sections of whole roots at lower magnification. The ventral root axons in the NF-M– and NF-M/H– mutants appear shrunken and frequently irregular in shape. In the dorsal roots only axons in the NF-M/H– mutant are affected by the atrophic process. Bar, 10 μm.
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Figure 1: Axonal morphology in dorsal and ventral roots of old NF- mutant animals. Light microscopy of toluidine blue–stained cross sections of L4 dorsal (A, C, E, and G) or L4 ventral (B, D, F, and H) roots from 2-yr-old wild-type (A and B), NF-M– mutant (C and D), NF-H– mutant (E and F), or NF-M/H– mutant (G and H) mice. Insets show cross sections of whole roots at lower magnification. The ventral root axons in the NF-M– and NF-M/H– mutants appear shrunken and frequently irregular in shape. In the dorsal roots only axons in the NF-M/H– mutant are affected by the atrophic process. Bar, 10 μm.

Mentions: By contrast, many of the ventral lumbar roots in 2-yr-old NF-M and essentially all of the lumbar ventral roots in the 2-yr-old NF-M/H– animals showed pathological changes. Examples of lumbar ventral roots from wild-type, NF-M–, NF-H–, and NF-M/H– mutant animals are shown in Fig. 1. Myelinated axons in the NF-M and NF-M/H mice were frequently irregular in shape and appeared shrunken and collapsed, resulting in axonal profiles that were dramatically smaller than wild-type axons. In the NF-M/H– mutants occasional dystrophic axons with accumulations of cellular organelles and multilamellar membranous profiles could also be seen. Occasionally, giant ballooned axons could also be seen in NF-M/H–deficient roots. More rarely, degenerating profiles could also be seen in the NF-M– mutants. However, such changes occurred in <1% of the axonal populations in either mutant, although they were never observed in the controls. There was no evidence in either mutant of macrophage infiltration or other features of Wallerian degeneration. Accompanying the axonal shrinkage and collapse there was frequently an expansion of the endoneurial space.


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 morphology in dorsal and ventral roots of old NF- mutant animals. Light microscopy of toluidine blue–stained cross sections of L4 dorsal (A, C, E, and G) or L4 ventral (B, D, F, and H) roots from 2-yr-old wild-type (A and B), NF-M– mutant (C and D), NF-H– mutant (E and F), or NF-M/H– mutant (G and H) mice. Insets show cross sections of whole roots at lower magnification. The ventral root axons in the NF-M– and NF-M/H– mutants appear shrunken and frequently irregular in shape. In the dorsal roots only axons in the NF-M/H– mutant are affected by the atrophic process. Bar, 10 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199745&req=5

Figure 1: Axonal morphology in dorsal and ventral roots of old NF- mutant animals. Light microscopy of toluidine blue–stained cross sections of L4 dorsal (A, C, E, and G) or L4 ventral (B, D, F, and H) roots from 2-yr-old wild-type (A and B), NF-M– mutant (C and D), NF-H– mutant (E and F), or NF-M/H– mutant (G and H) mice. Insets show cross sections of whole roots at lower magnification. The ventral root axons in the NF-M– and NF-M/H– mutants appear shrunken and frequently irregular in shape. In the dorsal roots only axons in the NF-M/H– mutant are affected by the atrophic process. Bar, 10 μm.
Mentions: By contrast, many of the ventral lumbar roots in 2-yr-old NF-M and essentially all of the lumbar ventral roots in the 2-yr-old NF-M/H– animals showed pathological changes. Examples of lumbar ventral roots from wild-type, NF-M–, NF-H–, and NF-M/H– mutant animals are shown in Fig. 1. Myelinated axons in the NF-M and NF-M/H mice were frequently irregular in shape and appeared shrunken and collapsed, resulting in axonal profiles that were dramatically smaller than wild-type axons. In the NF-M/H– mutants occasional dystrophic axons with accumulations of cellular organelles and multilamellar membranous profiles could also be seen. Occasionally, giant ballooned axons could also be seen in NF-M/H–deficient roots. More rarely, degenerating profiles could also be seen in the NF-M– mutants. However, such changes occurred in <1% of the axonal populations in either mutant, although they were never observed in the controls. There was no evidence in either mutant of macrophage infiltration or other features of Wallerian degeneration. Accompanying the axonal shrinkage and collapse there was frequently an expansion of the endoneurial space.

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