Myelination and regional domain differentiation of the axon

Abstract

During evolution, as organisms increased in complexity and function, the need for the ensheathment and insulation of axons by glia became vital for faster conductance of action potentials in nerves. Myelination, as the process is termed, facilitates the formation of discrete domains within the axolemma that are enriched in ion channels, and macromolecular complexes consisting of cell adhesion molecules and cytoskeletal regulators. While it is known that glia play a substantial role in the coordination and organization of these domains, the mechanisms involved and signals transduced between the axon and glia, as well as the proteins regulating axo-glial junction formation remain elusive. Emerging evidence has shed light on the processes regulating myelination and domain differentiation, and key molecules have been identified that are required for their assembly and maintenance. This review highlights these recent findings, and relates their significance to domain disorganization as seen in several demyelinating disorders and other neuropathies.

Fig. 1

Domain organization in myelinated PNS nerve fibers. Teased sciatic nerve fibers from wild-type (^+/+; a), Caspr null (Caspr^-/- ;b), and Neurofascin^NF155 (NF155) specific null mice (Cnpcre;Nfasc^Flox; c) mice immunostained with antibodies against Kv1.1 (red), Caspr (blue), and Neurofascin 186 (NF186; green). In wild-type nerve fibers, localization of Kv1.1 fluorescence is restricted to the juxtaparanode. Caspr staining marks the paranode and NF186 is a marker of the nodal region. In Caspr null fibers, the lack of paranodal axo–glial junctions results in the diffusion of potassium channels into the paranode, as evident by the presence of Kv1.1 fluorescence adjacent to NF186 staining at the node (b). Loss of NF155 expression results in the lack of Caspr fluorescence at the paranode and the redistribution of potassium channels into the paranodal region, similar to Caspr mutants (c). In both mutants, the node remains unaltered as indicated by NF186 fluorescence

Fig. 2

Comparative ultrastructure of Drosophila and mouse unmyelinated and myelinated nerve fibers. (a) Cross-sections of peripheral nerve fibers from Drosophila show the inner glia (G) ensheathing axons (a). Electron dense, ladder-like structures (arrow) known as septate junctions form between the outer perineurial (P) and the inner ensheathing glial cell (G) membranes (m) of Drosophila (arrowheads, D). Electron micrograph cross-section of a Remak bundle in the mouse peripheral nerve (b). Remak bundles consist of several small diameter axons (a) that are ensheathed by a single nonmyelinating Schwann cell. These fibers do not acquire myelination, and are similar in structure to Drosophila nerve fibers. Ultrastructure of a single myelinated mouse peripheral nerve fiber in cross-section (c). The continual wrapping of the Schwann cell myelin membrane (my) forms a multilamellar layer that is electron dense. A longitudinal section of the paranodal region of a myelinated axon (a) shows the septate-like junctions that form between the myelin loops (ml) and the underlying axolemma. Scale bars: (a) 2 μm; (b) 1 μm; (c) 0.5 μm; (d, e) 0.2 μm

Fig. 3

Major components of septate junctions in Drosophila and mouse. The domain structure of Drosophila Nrx IV, Contactin, Neuroglian, and Coracle, and their vertebrate counterparts in mouse, Caspr, Contactin, NF155, and Protein 4.1B reveals significant homology between these proteins (a). Schematic representation of the proteins involved in the formation of the paranodal axo–glial septate junctions in mouse (b). NF155 is expressed strictly in the myelinating glial within the paranodal loops. The presence of a FERM binding domain within NF155 predicts an interaction with a FERM protein, which may mediate signaling to the glial cytoskeleton. NF155 is hypothesized to bind to either Caspr or Contactin, but the exact mechanisms are yet unknown