Increasing neurofilament subunit NF-M expression reduces axonal NF-H, inhibits radial growth, and results in neurofilamentous accumulation in motor neurons.
The carboxy-terminal tail domains of neurofilament subunits neurofilament NF-M and NF-H have been postulated to be responsible for the modulation of axonal caliber. To test how subunit composition affects caliber, transgenic mice were generated to increase axonal NF-M. Total neurofilament subunit content in motor and sensory axons remained essentially unchanged, but increases in NF-M were offset by proportionate decreases in both NF-H and axonal cross-sectional area. Increase in NF-M did not affect the level of phosphorylation of NF-H. This indicates that (a) in vivo NF-H and NF-M compete either for coassembly with a limiting amount of NF-L or as substrates for axonal transport, and (b) NF-H abundance is a primary determinant of axonal caliber. Despite inhibition of radial growth, increase in NF-M and reduction in axonal NF-H did not affect nearest neighbor spacing between neurofilaments, indicating that cross-bridging between nearest neighbors does not play a crucial role in radial growth. Increase in NF-M did not result in an overt phenotype or neuronal loss, although filamentous swellings in perikarya and proximal axons of motor neurons were frequently found.
Wong
P C
PC
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Marszalek
J
J
Crawford
T O
TO
Xu
Z
Z
Hsieh
S T
ST
Griffin
J W
JW
Cleveland
D W
DW
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D002450:Cell Communication; D002455:Cell Division; D007382:Intermediate Filaments / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000502:physiology* / Q000648:ultrastructure