Review
Molecular domains of myelinated axons

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Abstract

Myelinated axons are organized into specific domains as the result of interactions with glial cells. Recently, distinct protein complexes of cell adhesion molecules, Na+ channels and ankyrin G at the nodes, Caspr and contactin in the paranodes, and K+ channels and Caspr2 in the juxtaparanodal region have been identified, and new insights into the role of the paranodal junctions in the organization of these domains have emerged.

Introduction

Myelinated fibers are organized into distinct domains: the node of Ranvier, the paranodal and juxtaparanodal regions, and the internode [[1]2radical dot]. This domain organization (shown schematically in Fig. 1, Fig. 2) is critical for the efficient conduction of nerve impulses via saltatory conduction and results from complex and poorly understood interactions between axons and myelinating glial cells. Recent studies have clarified the unique molecular composition of these axonal domains, demonstrating the presence of several protein complexes which include Na+ channels, ankyrin G and cell adhesion molecules (CAMs) at the nodes, contactin-associated protein (Caspr) and contactin at the paranodes, and K+ channels and Caspr2 at the juxtaparanodal region. As discussed below, these studies provide new insights into the generation and maintenance of functional domains along myelinated axons.

Section snippets

The initial segments and nodes of Ranvier

These domains share many features in common, notably an enormous enrichment of voltage-gated Na+ channels that are responsible for inward current flow. A major channel subtype at the nodes was recently demonstrated to be Nav1.6 in both sensory and motor axons of the adult peripheral nervous system (PNS) and central nervous system (CNS) [3], [4]. As nodes of mice deficient in Nav1.6 conduct action potentials and can be stained with a pan-specific Na+ channel antibody [3], other channel isotypes

Paranodes

On either sides of the node of Ranvier, the compact myelin lamellae open up into a series of cytoplasmic loops that spiral around, closely appose and form a series of septate-like junctions with the axon (see Fig. 2). The paranodal junctions, which are interposed between the node and juxtaparanode, have been proposed to serve the following functions: first, to anchor myelin loops to the axon; second, to form a partial diffusion barrier into the periaxonal space; and third, to demarcate axonal

Juxtaparanodes

This region of the axon is just under the compact myelin sheath beyond the innermost paranodal junction and may therefore be considered a specialized portion of the internode. The delayed-rectifier K+ channels Kv1.1, Kv1.2 and their Kvβ2 subunit are enriched in the juxtaparanodes and may promote repolarization and maintain the internodal resting potential [16], [17], [18]. The hyperexcitability observed in the nerves of Kv1.1-null mice indicates that these channels may also prevent ectopic

Internodal specialization

No proteins are known to be specifically enriched in the internode, consistent with the lack of intramembranous particles observed by freeze-fracture studies. An exception is that components of the paranode and juxtaparanode, for example Caspr, contactin, Kv1.1, and Kv1.2, extend into the internode as a thin spiral apposed to the inner mesaxon; they are also found apposed to the Schmidt–Lanterman clefts of the myelinating glial cells [[12]21radical dot].

Generation and maintenance of specialized domains

Dynamic changes in the expression and distribution of Na+ and K+ channels on axons occur during development. In particular, these channels cluster at the node and juxtaparanode respectively during myelination and disperse following demyelination, indicating that myelinating glia play a key role in the generation and maintenance of axonal domains [22]. Recent studies have focused on characterizing the glial signals and the role of intrinsic axonal determinants involved in this remarkable

Domain formation: glial signals versus intrinsic determinants

Two related questions have arisen: first, are the requisite glial signals soluble or contact-dependent; and second, are the locations of the nodes of Ranvier determined by the glial cell or intrinsically specified by the axon? These distinct mechanisms are shown schematically in Fig. 3. Important insights into both questions have been provided by analyses of the initial events of node formation. In the PNS, Na+ channels appear to first cluster adjacent to the edges of Schwann cells at the onset

Domain formation: temporal and functional relationships

Is the formation of the node of Ranvier and that of neighboring axonal domains interrelated, or do these domains form independently? Freeze-fracture studies of developing peripheral nerves have demonstrated that paranodal junctions form in a specific sequence, beginning closest to the node and then extending inward [26]. These studies were interpreted as suggesting that clustering of Na+ channels at the node depends on paranodal junction formation; an alternate interpretation is that as the

Mechanisms of domain formation

Recent studies have revealed that each of these domains contains a unique set of CAMs that exist as multi-protein complexes; in the node and juxtaparanodes, these complexes are linked to ion channels via scaffolding molecules in the cytoplasm. These complexes, in turn, are likely to be recruited to these sites as a consequence of extracellular interactions with components of the ECM and receptors on glial processes and, potentially, through interactions with the axon cytoskeleton. The

Na+ channels at the nodes and initial segments

At the nodes and initial segments, Na+ channels are believed to be in a macromolecular complex with ankyrin G and the CAMs NrCAM and neurofascin (see Fig. 4a). The sequence of complex assembly has been analyzed during the development of peripheral nodes [23]. Neurofascin and NrCAM were found to cluster first, suggesting that these CAMs initiate node formation, and ankyrin and Na+ channels are subsequently recruited to these sites. Binding of ankyrin to these CAMs, and therefore its recruitment

Caspr at the paranodes

The localization of Caspr and the development of the septate junctions is strictly dependent on the maturation of the myelinated fiber, suggesting a role for the glial cells in this process [13], [27]. Further support is provided by the localization of Caspr to the discrete regions of the axolemma that appose the mesaxon and Schmidt–Lanterman incisures of myelinating Schwann cells [21radical dot]. The extracellular region of Caspr is a mosaic of domains implicated in mediating protein–protein and

K+ channels at the juxtaparanodes

Subcellular targeting and localized clustering of ion channels was proposed to be regulated by scaffolding molecules such as members of the PSD95 family [50]. Although the presence of a PSD95-like protein in the juxtaparanodes along with K+ channels was recently demonstrated [51], the exact molecular identity of this protein is still unknown. Insight into the mechanism by which ensheathing glial cells regulate the localization of K+ channels was recently provided with the identification of

Conclusions

Recent studies implicate intrinsic and extrinsic signals in the generation, localization and maintenance of specialized microdomains of myelinated axons. It is likely that, within the axon, multi-protein complexes organized by scaffolding molecules are appropriately targeted via interactions with glial ligands. Given the rapid pace of progress, the molecular identity of the glial signals, as well as an understanding of the mechanisms of channel clustering and node formation, is likely to emerge

Update

The work described as Rios et al., Soc Neurosci Abstr 1999, 401.5 is now in press [56radical dot57radical dot].

Acknowledgements

Due to space limitations, we regret any omissions in citing other relevant publications. We thank George Zanazzi, Jack Rosenbluth and Steve Lambert for helpful comments on the manuscript and Jill Gregory for assistance in preparing the figures. Work from the authors’ laboratories cited in this review has been supported by grants from the National Institutes of Health and from the National Multiple Sclerosis Society. E Peles is Incumbent of the Madeleine Haas Russell Career Development Chair.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • radical dot of special interest

  • radical dotradical dot of outstanding interest

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