Myelinated fibers are organized into distinct domains that are necessary for saltatory conduction. These domains include the nodes of Ranvier and the flanking paranodal regions where glial cells closely appose and form specialized septate-like junctions with axons. These junctions contain a Drosophila Neurexin IV-related protein, Caspr/Paranodin (NCP1). Mice that lack NCP1 exhibit tremor, ataxia, and significant motor paresis. In the absence of NCP1, normal paranodal junctions fail to form, and the organization of the paranodal loops is disrupted. Contactin is undetectable in the paranodes, and K(+) channels are displaced from the juxtaparanodal into the paranodal domains. Loss of NCP1 also results in a severe decrease in peripheral nerve conduction velocity. These results show a critical role for NCP1 in the delineation of specific axonal domains and the axon-glia interactions required for normal saltatory conduction.

Specialized paranodal junctions form between the axon and the closely apposed paranodal loops of myelinating glia. They are interposed between sodium channels at the nodes of Ranvier and potassium channels in the juxtaparanodal regions; their precise function and molecular composition have been elusive. We previously reported that Caspr (contactin-associated protein) is a major axonal constituent of these junctions (Einheber et al., 1997). We now report that contactin colocalizes and forms a cis complex with Caspr in the paranodes and juxtamesaxon. These proteins coextract and coprecipitate from neurons, myelinating cultures, and myelin preparations enriched in junctional markers; they fractionate on sucrose gradients as a high-molecular-weight complex, suggesting that other proteins may also be associated with this complex. Neurons express two contactin isoforms that differ in their extent of glycosylation: a lower-molecular-weight phosphatidylinositol phospholipase C (PI-PLC)-resistant form is associated specifically with Caspr in the paranodes, whereas a higher-molecular-weight form of contactin, not associated with Caspr, is present in central nodes of Ranvier. These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr. Treatment of myelinating cocultures of Schwann cells and neurons with RPTP␤-Fc, a soluble construct containing the carbonic anhydrase domain of the receptor protein tyrosine phosphatase ␤ (RPTP␤), a potential glial receptor for contactin, blocks the localization of the Caspr/contactin complex to the paranodes. These results strongly suggest that a preformed complex of Caspr and contactin is targeted to the paranodal junctions via extracellular interactions with myelinating glia.

The node of Ranvier is a distinct domain of myelinated axons that is highly enriched in sodium channels and is critical for impulse propagation. During development, the channel subtypes expressed at the node undergo a transition from Nav1.2 to Nav1.6. Specialized junctions that form between the paranodal glial membranes and axon flank the nodes and are candidates to regulate their maturation and delineate their boundaries. To investigate these roles, we characterized node development in mice deficient in contactin-associated protein (Caspr), an integral junctional component. Paranodes in these mice lack transverse bands, a hallmark of the mature junction, and exhibit progressive disruption of axon-paranodal loop interactions in the CNS. Caspr mutant mice display significant abnormalities at central nodes; components of the nodes progressively disperse along axons, and many nodes fail to mature properly, persistently expressing Nav1.2 rather than Nav1.6. In contrast, PNS nodes are only modestly longer and, although maturation is delayed, eventually all express Nav1.6. Potassium channels are aberrantly clustered in the paranodes; these clusters are lost over time in the CNS, whereas they persist in the PNS. These findings indicate that interactions of the paranodal loops with the axon promote the transition in sodium channel subtypes at CNS nodes and provide a lateral diffusion barrier that, even in the absence of transverse bands, maintains a high concentration of components at the node and the integrity of voltage-gated channel domains.

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