The Nodes of Ranvier: Molecular Assembly and Maintenance

Abstract

Action potential (AP) propagation in myelinated nerves requires clustered voltage gated sodium and potassium channels. These channels must be specifically localized to nodes of Ranvier where the AP is regenerated. Several mechanisms have evolved to facilitate and ensure the correct assembly and stabilization of these essential axonal domains. This review highlights the current understanding of the axon intrinsic and glial extrinsic mechanisms that control the formation and maintenance of the nodes of Ranvier in both the peripheral nervous system (PNS) and central nervous system (CNS).A xons conduct electrical signals, called action potentials (APs), among neurons in a circuit in response to sensory input, and between motor neurons and muscles. In mammals and other vertebrates, many axons are myelinated. Myelin, made by Schwann cells and oligodendrocytes in the peripheral nervous system (PNS) and central nervous system (CNS), respectively, is a multilamellar sheet of glial membrane that wraps around axons to increase transmembrane resistance and decrease membrane capacitance. Although myelin is traditionally viewed as a passive contributor to nervous system function, it is now recognized that myelinating glia also play many active roles including regulation of axon diameter, axonal energy metabolism, and the clustering of ion channels at gaps in the myelin sheath called nodes of Ranvier. Together, the active and passive properties conferred on axons by myelin, result in axons with high AP conduction velocities, low metabolic demands, and reduced space requirements as compared with unmyelinated axons. Thus, myelin and the clustering of ion channels in axons permitted the evolution of the complex nervous systems found in vertebrates. This review highlights the current understanding of the axonal intrinsic and glial extrinsic mechanisms that control the formation and maintenance of the nodes of Ranvier in both the PNS and CNS.

Severity of Demyelinating and Axonal Neuropathy Mouse Models Is Modified by Genes Affecting Structure and Function of Peripheral Nodes

“…However, our point is not to make a direct case for NRCAM or SCN8A as human disease modifiers for CMT (indeed, their clinical associations are more severe than the “subclinical” mouse mutations we are describing) but instead to use them as a demonstration of the principle that variants that impact nodes will lead to more severe CMT phenotypes. Such variants may include any of the key components of the node of Ranvier (see Rasband and Peles, 2015 for review). Although the frequency of such modifiers is currently unknown, as genetic diagnostic sequencing improves, variants in such genes in patients diagnosed with CMT can be tested for correlation with the disease severity, which could improve the prognostic accuracy for disease severity and progression.…”

“…The immunoglobulin (Ig) superfamily-member cell adhesion molecule Nrcam (Neuroglial-related cell adhesion molecule) is part of a transmembrane complex at nodes. During development, NRCAM and gliomedin in the Schwann cell establish a heminode in the axon at the boundary of the maturing Schwann cell, which then fuses into a mature node (Eshed-Eisenbach and Peles, 2013; Rasband and Peles, 2015; Feinberg et al, 2010). The loss of Nrcam results in delayed formation of nodes, and occasional “split nodes” in adult peripheral nerves, but no obvious signs of neuromuscular dysfunction (Amor et al, 2014; Custer et al, 2003).…”

Nodes, paranodes and neuropathies

“…At the juxtaparanode, a complex of Caspr2 (on the axon), contactin-2 (CNTN2, also known as transient axonal glycoprotein 1; TAG1, expressed on both the axonal and glial membranes13), PSD93/95 and 4.1B link the VGKCs to the axonal spectrin cytoskeleton 14. These VGKCs mostly comprised Kv1.1 and Kv1.2 subtypes, and are involved in the repolarisation phase of action potentials.…”

Schwann Cell Myelination

“…As a consequence, the axon is especially vulnerable to loss of myelin, which significantly contributes to the morbidity of dysmyelinating and demyelinating disorders. The role of myelin on the domain organization of axons is considered in detail elsewhere in the literature (Rasband and Peles 2015). Here, we briefly highlight other effects of myelination on the axon.…”

“…The remaining 1% corresponds to the nodal region, including the node itself, the flanking paranodes, and juxtaparanodes. Protein components for these domains are discussed in detail elsewhere ; see also Rasband and Peles 2015). The outer, abaxonal membrane lies adjacent to and mediates interactions with laminin in the basal lamina, notably the integrins, including a6b1, which is expressed initially, and a6b4 and b dystroglycan, which are up-regulated with myelination (Einheber et al 1992;Previtali et al 2003).…”