title: NF-M is an essential target for the myelin-directed "outside-in" signaling cascade that mediates radial axonal growth.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Garcia
authors.forename: Christian S
authors.initials: CS
authors.lastname: Lobsiger
authors.forename: Sameer B
authors.initials: SB
authors.lastname: Shah
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Deerinck
authors.forename: John
authors.initials: J
authors.lastname: Crum
authors.forename: Darren
authors.initials: D
authors.lastname: Young
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Ward
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Crawford
authors.forename: Takahiro
authors.initials: T
authors.lastname: Gotow
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Calcutt
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000200:Action Potentials / Q000502:physiology; D020816:Amino Acid Motifs; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009043:Motor Activity; D009186:Myelin Sheath / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016900:Neurofilament Proteins; D021122:Protein Subunits; C051774:neurofilament protein H; C061195:neurofilament protein M