Nr-CAM and neurofascin interactions regulate ankyrin G and sodium channel clustering at the node of Ranvier

Voltage-dependent sodium (Na+) channels are highly concentrated at nodes of Ranvier in myelinated axons and play a key role in promoting rapid and eff icient conduction of action potentials by saltatory conduction. The molecul ar mechanisms that direct their localization to the node are not well under stood but are believed to involve contact-dependent signals from myelinatin g Schwann cells [1] and interactions of Na+ channels with the cytoskeletal protein, ankyrin G [2]. Two cell adhesion molecules (CAMs) expressed at the axon surface, Nr-CAM and neurofascin, are also linked to ankyrin G and acc umulate at early stages of node formation, suggesting that they mediate con tact-dependent Schwann cell signals to initiate node development [3]. To ex amine the potential role of Nr-CAM in this process, we treated myelinating cocultures of DRG (dorsal root ganglion) neurons and Schwann cells with an Nr-CAM-Fc (Nr-Fc) fusion protein. Nr-Fc had no effect on initial axon-Schwa nn cell interactions, including Schwann cell proliferation, or on the exten t of myelination, but it strikingly and specifically inhibited Na+ channel and ankyrin G accumulation at the node. Nr-Fc bound directly to neurons and clustered and coprecipitated neurofascin expressed on axons. These results provide the first evidence that neurofascin plays a major role in the form ation of nodes, possibly via interactions with Nr-CAM.