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Published 8 December 2003. doi:10.1083/jcb.200308159
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© The Rockefeller University Press, 0021-9525/2003/12/1011 $8.00
The Journal of Cell Biology, Volume 163, Number 5, 1011-1020

Article

NF-M is an essential target for the myelin-directed "outside-in" signaling cascade that mediates radial axonal growth



Michael L. Garcia1,2,3, Christian S. Lobsiger1,2, Sameer B. Shah2,6, Tom J. Deerinck4, John Crum4, Darren Young1, Christopher M. Ward1,2, Thomas O. Crawford7, Takahiro Gotow8, Yasuo Uchiyama9, Mark H. Ellisman4, Nigel A. Calcutt5 and Don W. Cleveland1,2,3

1 Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093
2 Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093
3 Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093
4 National Center for Microscopy and Imaging Research, University of California at San Diego, La Jolla, CA 92093
5 Department of Pathology, University of California at San Diego, La Jolla, CA 92093
6 Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093
7 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
8 Laboratory of Cell Biology, College of Nutrition, Koshien University, Hyogo 665-0006, Japan
9 Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan

Address correspondence to Don W. Cleveland, Ludwig Institute for Cancer Research, CMM-E/Room 3080, 9500 Gilman Drive, La Jolla, CA 92093-0670. Tel.: (858) 534-7811. Fax: (858) 534-7659. email: dcleveland{at}ucsd.edu

Neurofilaments are essential for acquisition of normal axonal calibers. Several lines of evidence have suggested that neurofilament-dependent structuring of axoplasm arises through an "outside-in" signaling cascade originating from myelinating cells. Implicated as targets in this cascade are the highly phosphorylated KSP domains of neurofilament subunits NF-H and NF-M. These are nearly stoichiometrically phosphorylated in myelinated internodes where radial axonal growth takes place, but not in the smaller, unmyelinated nodes. Gene replacement has now been used to produce mice expressing normal levels of the three neurofilament subunits, but which are deleted in the known phosphorylation sites within either NF-M or within both NF-M and NF-H. This has revealed that the tail domain of NF-M, with seven KSP motifs, is an essential target for the myelination-dependent outside-in signaling cascade that determines axonal caliber and conduction velocity of motor axons.

Key Words: myelin; neurofilaments; phosphorylation; axon caliber; radial growth

Abbreviations used in this paper: cdk-5, cyclin-dependent kinase 5; ERK1/2, extracellular signal–regulated protein kinase 1/2; MAG, myelin-associated glycoprotein; NF-L, -M, and -H, neurofilament light, medium, and heavy.


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