The Role of the Ankyrin-Binding Protein NrCAM in Node of Ranvier Formation

Abstract

Molecular events involved in Na+ channel clustering at the node of Ranvier have been investigated during early development. NrCAM, an ankyrinG-binding protein, precedes Na+ channels at cluster sites adjacent to the tips of Schwann cell processes. Both Na+ channel and ankyrinG sequestration at developing nodes are delayed in NrCAM null mutants. The action of NrCAM is manifest locally at individual nodes, rather than affecting overall neuronal expression, and is linked to glial interactions. During remyelination, Na+ channel clusters at new nodes are initially labile, and anchoring to the cytoskeleton appears to grow progressively with time. The distance between Na+ channel clusters across remyelinating Schwann cells (nascent internodes) increases markedly from 83 to 274 microm during node formation, arguing against schemes in which the loci of nodes are fixed in advance by the axon. A hypothesis for node formation in which axonal Na+ channels move by lateral diffusion from regions of Schwann cell contact, with clustering dependent on linkage to the cytoskeleton by ankyrinG, is proposed and tested in a computational model. To match experimental measurements, this latter reaction needs fast kinetics, and the early arrival of NrCAM is postulated to contribute to this requirement.

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

“…In contrast, sodium channel ␤3 subunits do not appear to interact with ␤1. Nf155 and NrCAM are important for formation and maintenance of both CNS and PNS nodes of Ranvier (2,3,6). ␤2 is critical for sodium channel cell surface expression in vitro and in vivo (19,46,47).…”

“…Recent evidence has shown a role for NrCAM and Nf186 in delineating presumptive PNS nodes of Ranvier prior to sodium channel and ankyrin G clustering (2,18). NrCAM (Ϫ/Ϫ) mice exhibit a delay in nodal development as well as a delay in the localization of ankyrin G to PNS nodal areas (2).…”

“…The axo-glial complex in myelinated axons is composed of a nodal gap region that contains high density clusters of voltagegated sodium channels and a juxtaparanodal region that contains voltage-gated potassium channels (1)(2)(3)(4)(5)(6). The nodal gap and the juxtaparanode are separated by the paranode, a region containing septate-like junctions composed of cell adhesion molecules (CAMs) 1 that act as diffusion barriers to ion channel movement (2, 6 -8).…”

“…Sodium channels are clustered at high density in axon initial segments and nodes of Ranvier of myelinated axons, where they co-localize with members of the Ig superfamily of CAMs such as contactin, NrCAM, and neurofascin 186 (Nf186) (2,17,18).…”

“…In sciatic nerve, Nf186 and NrCAM are early markers of nodal formation that cluster at presumptive nodes prior to sodium channels and ankyrin G (2,25). In the peripheral nervous system (PNS), Schwann cell contact at the beginning stages of myelin ensheathement is required for sodium channel clustering (26,27).…”