Axonal Neurofilaments Control Multiple Fiber Properties But Do Not Influence Structure or Spacing of Nodes of Ranvier

Abstract

In the vertebrate nervous system, axon calibers correlate positively with myelin sheath dimensions and electrophysiological parameters including action potential amplitude and conduction velocity. Neurofilaments, a prominent component of the neuronal cytoskeleton, are required by axons to support their normal radial growth. To distinguish between fiber features that arise in response to absolute axon caliber and those that are under autonomous control, we investigated transgenic mice in which neurofilaments are sequestered in neuronal cell bodies. The neurofilament deficient axons in such mice achieve mature calibers only 50% of normal and have altered conduction properties. We show here that this primary axonal defect also induces multiple changes in myelin sheath composition and radial dimensions. Remarkably, other fundamental fiber features, including internodal spacing and the architecture and composition of nodes of Ranvier, remain unaltered. Thus, many fiber characteristics are controlled through mechanisms operating independently of absolute axon caliber and the neurofilament cytoskeleton.

Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E

“…A previous study of nodal architecture in NF-deficient mice showed normal placement, organization, and physical dimensions of nodes of Ranvier. 17 Our results demonstrated that sodium channels and Caspr are correctly localized in patients with CMT2E (figure 4), confirming that, despite the axonal NF deficiency, the molecular architecture of nodal and paranodal regions is not impaired in CMT2E. This observation supports the hypothesis that NFs, as cytoskeletal components of the internodal domain of axons, are not required to position nodal and paranodal molecules.…”

Application of Raman spectroscopy for visualizing biochemical changes during peripheral nerve injuryin vitroandin vivo

“…The bands at 2853 and 2885 cm −1 are derived from lipids, 21,22 and peripheral nerve tissue is rich in lipids in myelin sheaths that surround axons to support neural electrical activity. [28][29][30][31] Myelin is supplied by Schwann cells and myelin lipids include sphingomyelin and the glycolipid galactocerebroside. Schwann cells had similar spectral patterns at 2851 and 2885 cm −1 and Raman spectra of sphingomyelin showed similar patterns to that of Schwann cells.…”

Neurofilaments at a glance

“…Although deletion of the phosphorylated tail domain of NFM inhibits radial growth of axons and reduces their conduction velocities (Garcia et al, 2003;Rao et al, 2003), mice expressing NFM subunits that lack phosphorylation at KSP (Lys-Ser-Pro) sites along the tail domain have normal axon calibers and conduction velocities (Garcia et al, 2009), indicating that the NFM tail domain but not tail phosphorylation is crucial for axon radial growth. Decreased axon caliber that is accompanied by reduced conduction velocity has been observed in mutant Japanese quail that lack NFs because of a nonsense mutation in the NFL gene (Sakaguchi et al, 1993), in transgenic mice expressing a NFH-b-galactosidase fusion protein that interferes with NF transport into axons (Perrot et al, 2007), and in knockout mice that lack Nefl or Nefm (Križ et al, 2000). However, normal axonal caliber but decreased conduction velocity is observed in Nefh-null mice, indicating that NFs have roles beyond being determinants of the physical dimensions of axons (Križ et al, 2000).…”