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The local differentiation of myelinated axons at nodes of Ranvier

Key Points

  • The nodes of Ranvier are specialized axonal segments that lack myelin, allowing the saltatory conduction of action potentials. Important progress has been made in unravelling the fine structure of the nodal environs and in understanding the formation of a node.

  • The myelinated region that is contiguous with the node has been divided to three regions — paranode, juxtaparanode and internode. These regions and the node itself have distinct molecular signatures that are closely related to their function.

  • The node of Ranvier is rich in Na+ channels, which are crucial for action potential conduction, adhesion molecules such as Nrcam and Nf186, and cytoskeletal adaptor proteins, such as ankyrin G and spectrin βIV. In addition, Schwann cell microvilli cover the nodal gap in the peripheral nervous system (PNS), whereas astrocytic processes occupy the equivalent space in the central nervous system (CNS).

  • The paranode consists of cytoplasm-filled glial loops that wrap around the axon. In this region, the axonal membrane is rich in a complex formed by the recognition molecules Caspr and contactin. These molecules bind a series of adhesion molecules and proteins such as 4.1B, which might be important for the attachment of the complex to the cytoskeleton. Moreover, the position of the Caspr/contactin complex to the paranodal junction seems to depend on glial molecules such as NF155.

  • The juxtaparanode is a short zone next to the innermost paranodal junction. The axonal membrane in this region has a high concentration of K+ channels, and harbours molecules such as Caspr2 and Tag1, which are important for localizing the K+ channels to this region. Tag1 is also present in the glial cell, and its homophilic interaction might be important for the structural integrity of this area.

  • The most conspicuous characteristic of the internodes in the PNS is the presence of longitudinal strands of intramembranous particles that contain molecules that are present in the paranode and the juxtaparanode. Their localization might also depend on the glial membrane. These strands are not found in the CNS.

  • During the development of myelinated nerves, the different nodal domains form gradually; Na+ channels are first clustered at the nodes, followed by the formation of the paranodal junction, and later on by the clustering of K+ channels at the juxtaparanode. This timing seems to depend on the interactions of the axon with the glial cell.

  • In addition to the requirement for specific molecular interactions, the development of the different domains of the nodal environs depends on the segregation of molecules to the different compartments. This segregation depends on specific sorting and anchoring mechanisms that might involve molecular filters and barriers in the plane of the membrane.

  • Although many of the elements that participate in the assembly of the node and its environs have been identified, it is to be expected that there are many more. To identify them and understand the logic of their assembly is one of the important challenges for the field.

Abstract

Efficient and rapid propagation of action potentials in myelinated axons depends on the molecular specialization of the nodes of Ranvier. The nodal region is organized into several distinct domains, each of which contains a unique set of ion channels, cell-adhesion molecules and cytoplasmic adaptor proteins. Voltage-gated Na+ channels — which are concentrated at the nodes — are separated from K+ channels — which are clustered at the juxtaparanodal region — by a specialized axoglial contact that is formed between the axon and the myelinating cell at the paranodes. This local differentiation of myelinated axons is tightly regulated by oligodendrocytes and myelinating Schwann cells, and is achieved through complex mechanisms that are used by another specialized cell–cell contact — the synapse.

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Figure 1: Structure of myelinated axons.
Figure 2: Molecular composition of the nodal domains.
Figure 3: Arrangement of the nodal environ in various mutant mice.
Figure 4: A computational model describing a role for juxtaparanodal K+ channels in myelinated fibres.
Figure 5: Possible mechanisms involved in node formation.

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Acknowledgements

We thank many colleagues for their input and discussion. We are grateful to P. Shrager for his contribution of the computational model presented in Fig. 4. The work carried out in the authors' laboratory is supported by the National Multiple Sclerosis Society, the United States–Israel Science Foundation (BSF), the Minerva Foundation and the Israel Science Foundation. E.P. is an Incumbent of the Madeleine Haas Russell Career Development Chair.

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DATABASES

LocusLink

ankyrin G

Caspr

contactin

Cx29

dystroglycan

ezrin

moesin

neurexins

neurofascin

Nrcam

phosphacan

protein 4.1B

PSD-95

radixin

Schwanomin

spectrin βIV

TAG-1

tenascin-C

tenascin-R

versican

Glossary

TIGHT JUNCTION

A belt-like region of adhesion between adjacent cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing within the plane of the membrane.

ABAXONAL

Term that refers to the outermost layer of the myelin sheath.

TYPE I TRANSMEMBRANE PROTEIN

Molecule with a single transmembrane domain.

CIS INTERACTION

Term that refers to the interaction between molecules that are present in the same cell membrane, as opposed to an interaction in trans, in which the interacting molecules are present in opposing membranes.

LIPID RAFTS

Dynamic assemblies of cholesterol and sphingolipids in the plasma membrane.

MULTIPLE SCLEROSIS

A neurodegenerative disorder characterized by demyelination of central nervous system tracts. Symptoms depend on the site of demyelination and include sensory loss, weakness in leg muscles, speech difficulties, loss of coordination and dizziness.

FREEZE FRACTURE

An electron-microscopic method in which rapidly frozen tissue is cracked to produce a fracture plane through the specimen. The surface of the fracture plane is shadowed by a heavy metal, and the specimen is digested away to leave a replica that can be examined under the electron microscope.

DELAYED RECTIFIER K+ CHANNELS

Slowly activating and very slowly inactivating channels that preferentially pass K+ out of the cell.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs large, zona occludens 1).

ADAXONAL

Term that refers to the innermost layer of the myelin sheath.

GAP JUNCTIONS

Cellular specializations that allow the non-selective passage of small molecules between the cytoplasm of adjacent cells. They are formed by channels termed connexons — multimeric complexes of proteins known as connexins. Gap junctions are structural elements of electrical synapses.

SCHMIDT–LANTERMAN INCISURE

A cytoplasmic channel that interconnects the adaxonal and abaxonal layers of the myelin sheath.

LAMINA CRIBROSA

The supporting structure for the optic nerve at the point in which it leaves the eye.

CLAW PAW

Mutant mice in which peripheral myelination is disrupted, but central myelination is unaffected. The responsible gene has not been identified.

MYELIN-DEFICIENT RATS

Strain which the gene for the proteolipid protein is mutated, leading to defective myelination, tremors, ataxia and early death. ataxia, tremor and cerebral atrophy.

JIMPY

A mouse strain in which the gene for the proteolipid protein is mutated, leading to defective myelination and oligodendrocyte death.

SHIVERER

A mouse strain in which the gene for myelin basic protein is mutated, leading to a defect in myelination. These animals are characterized by the presence of ataxia, tremor and cerebral atrophy.

QUIVERING

A mouse strain in which the gene for spectrin βIV is mutated, leading to progressive ataxia, tremor, hindlimb paralysis and deafness.

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Poliak, S., Peles, E. The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci 4, 968–980 (2003). https://doi.org/10.1038/nrn1253

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