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

Author:

Garcia Michael L.123,Lobsiger Christian S.12,Shah Sameer B.24,Deerinck Tom J.5,Crum John5,Young Darren1,Ward Christopher M.12,Crawford Thomas O.6,Gotow Takahiro7,Uchiyama Yasuo8,Ellisman Mark H.5,Calcutt Nigel A.9,Cleveland Don W.123

Affiliation:

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. Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093

5. National Center for Microscopy and Imaging Research, University of California at San Diego, La Jolla, CA 92093

6. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205

7. Laboratory of Cell Biology, College of Nutrition, Koshien University, Hyogo 665-0006, Japan

8. Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan

9. Department of Pathology, University of California at San Diego, La Jolla, CA 92093

Abstract

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.

Publisher

Rockefeller University Press

Subject

Cell Biology

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