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