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Mechanisms of axon ensheathment and myelin growth

Key Points

  • The myelin sheath is one of the best studied mammalian membranes, not least because of its vital function, and also owing to its abundance and the ease of isolation of enriched myelin fractions. This review highlights four crucial stages of myelination, namely, the selection of axons and initiation of cell–cell interaction between these and glial cells, the establishment of stable intercellular contact and assembly of the nodes of Ranvier, regulation of myelin thickness and, finally, longitudinal extension of myelin segments in response to the lengthening of axons during postnatal growth.

  • The reasons why some axons are myelinated and others are not is still baffling. In general, a minimum calibre is required (1 μm) before an axon can be myelinated. It has recently been shown that nerve growth factor (NGF) might also have a role in regulating myelination. NGF stimulates myelination by Schwann cells but inhibits oligodendrocyte-mediated myelination, and these effects seem to be indirect — that is, the signals that affect myelination arise from axons in response to the binding of NGF to axonal tyrosine kinase TrkA receptors.

  • Myelin basic protein is synthesized in the growing myelin process from mRNA that is transported there in a microtubule-dependent fashion. The microfilament system also has a role through the small GTPase Rho, and intact microfilaments are essential for process extension and the expression of myelin-related genes.

  • Ensheathment by myelin-forming glia and the formation of nodes of Ranvier are almost certainly inextricably linked. Nevertheless, formation of the major adhesive junction between axons and glia, the paranodal axo–glial junction, is not essential for nodal formation, although it probably has a role in helping to maintain the tight clustering of nodal components in the mature nerve. It is still not certain that the mechanisms for the assembly of the axon initial segments are identical to those that operate at the node, despite their similar protein compositions.

  • The ratio of myelin thickness to axonal diameter is remarkably constant and axonally-derived neuregulin (NrgI type III) seems to have an important role, as myelin sheaths are thicker when it is over expressed. Brain-derived neurotrophic factor and the neurotrophin receptor p75 have also been implicated in regulating later stages of myelination, including myelin thickness. By contrast, the length of internodes, at least in the PNS, is regulated by Cajal bands in a Schwann cell autonomous fashion.

Abstract

The evolution of complex nervous systems in vertebrates has been accompanied by, and probably dependent on, the acquisition of the myelin sheath. Although there has been substantial progress in our understanding of the factors that determine glial cell fate, much less is known about the cellular mechanisms that determine how the myelin sheath is extended and stabilized around axons. This review highlights four crucial stages of myelination, namely, the selection of axons and initiation of cell–cell interactions between them and glial cells, the establishment of stable intercellular contact and assembly of the nodes of Ranvier, regulation of myelin thickness and, finally, longitudinal extension of myelin segments in response to the lengthening of axons during postnatal growth.

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Figure 1: Ensheathment of an axon by oligodendrocytes.
Figure 2: Myelination causes clustering of the sodium channel complex at nodes of Ranvier and axon initial segments.
Figure 3: Cajal bands form channels for mRNA transport in Schwann cells.

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Acknowledgements

Work in the authors' laboratory is supported by the Medical Research Council, the Wellcome Trust and the Multiple Sclerosis Society.

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Correspondence to Peter J. Brophy.

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DATABASES

Entrez Gene

Akt

BDNF

Caspr

CNP1

DRP2

Fyn

GDNF

KIF1B

KIF5A

MBP

NCAM

NrCAM

Nrg1

PI3K

PLCγ1

SHC

Src

S1P5

TrkA

FURTHER INFORMATION

Brophy's laboratory

Glossary

MULTIPLE SCLEROSIS

A disease of the CNS that is characterized by focal areas in which myelin is lost from axons, leading to axon degeneration.

NEUREGULINS

A family of receptor tyrosine kinases related to epidermal growth factor (EGF). The receptors for neuregulins are the ErbB family of tyrosine kinase transmembrane receptors.

LIPID RAFTS

Domains within plasma membranes believed to be enriched in cholesterol and glycolipids that are proposed to aid the delivery of subsets of membrane proteins to the plasma membrane and serve as sites for concentrating signalling molecules.

PARANODAL AXO–GLIAL JUNCTIONS

Major sites of physical interaction between myelin-forming glial cells and the axon that lie on either side of the nodes of Ranvier and are characterized by septate-like junctions.

Rho, Cdc42 AND Rac

Rho GTPases are small (20–30 kDa) GTP-binding proteins of the Ras superfamily and are divided into three main subgroups, Rho, Cdc42 and Rac, which have distinct effects on microfilament dynamics.

PERIAXIN

A protein of myelinating Schwann cells that is concentrated at zones of adhesion between the abaxonal (outermost) myelin lamella and the Schwann cell plasma membrane in a complex with DRP2 and dystroglycan.

CAJAL BANDS

Cytoplasmic channels that lie beneath the surface of the Schwann cell plasma membrane and that are separated from each other by the appositions formed by the periaxin–DRP2–dystroglycan complexes.

CHARCOT-MARIE-TOOTH DISEASE

An inherited degenerative neuropathy of the PNS that is caused by more than 30 different mutations. Although most forms are primarily demyelinating, loss of proper glial contact generally results in axonal degeneration.

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Sherman, D., Brophy, P. Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci 6, 683–690 (2005). https://doi.org/10.1038/nrn1743

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