Neurofilament subunit NF-H modulates axonal diameter by selectively slowing neurofilament transport

Joseph R. Marszalek, Toni L. Williamson, Michael K. Lee, Zuoshang Xu, Paul N. Hoffman, Mark W. Becher, Thomas O. Crawford, Don W. Cleveland

Research output: Contribution to journalArticle

Abstract

To examine the mechanism through which neurofilaments regulate the caliber of myelinated axons and to test how aberrant accumulations of neurofilaments cause motor neuron disease, mice have been constructed that express wild-type mouse NF-H up to 4.5 times the normal level. Small increases in NF-H expression lead to increased total neurofilament content and larger myelinated axons, whereas larger increases in NF-H decrease total neurofilament content and strongly inhibit radial growth. Increasing NF-H expression selectively slows neurofilament transport into and along axons, resulting in severe perikaryal accumulation of neurofilaments and proximal axonal swellings in motor neurons. Unlike the situation in transgenic mice expressing modest levels of human NF-H (Cote, F., J.F. Collard, and J.P. Julien. 1993. Cell. 73:35-46), even 4.5 times the normal level of wild-type mouse NF-H does not result in any overt phenotype or enhanced motor neuron degeneration or loss. Rather, motor neurons are extraordinarily tolerant of wild-type murine NF-H, whereas wild-type human NF-H, which differs from the mouse homolog at >160 residue positions, mediates motor neuron disease in mice by acting as an aberrant, mutant subunit.

Original languageEnglish (US)
Pages (from-to)711-724
Number of pages14
JournalJournal of Cell Biology
Volume135
Issue number3
DOIs
StatePublished - Nov 1996

ASJC Scopus subject areas

  • Cell Biology

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    Marszalek, J. R., Williamson, T. L., Lee, M. K., Xu, Z., Hoffman, P. N., Becher, M. W., Crawford, T. O., & Cleveland, D. W. (1996). Neurofilament subunit NF-H modulates axonal diameter by selectively slowing neurofilament transport. Journal of Cell Biology, 135(3), 711-724. https://doi.org/10.1083/jcb.135.3.711