Paranodal interactions regulate expression of sodium channel subtypes and provide a diffusion barrier for the node of Ranvier.
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.
Rios
Jose C
JC
Department of Cell Biology, and the Rusk Institute, New York University School of Medicine, New York, New York 10016, USA.
Rubin
Marina
M
St Martin
Mary
M
Downey
Ryan T
RT
Einheber
Steven
S
Rosenbluth
Jack
J
Levinson
S Rock
SR
Bhat
Manzoor
M
Salzer
James L
JL
D000367:Age Factors; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000172:deficiency / Q000235:genetics; D004058:Diffusion; D005614:Freeze Fracturing; D066298:In Vitro Techniques; D051662:Kv1.1 Potassium Channel; D051663:Kv1.2 Potassium Channel; D051379:Mice; D008817:Mice, Mutant Strains; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009900:Optic Nerve / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D015221:Potassium Channels / Q000096:biosynthesis; D024642:Potassium Channels, Voltage-Gated; D011901:Ranvier's Nodes / Q000378:metabolism* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D015222:Sodium Channels / Q000378:metabolism*
D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; C496947:Kcna1 protein, mouse; C496970:Kcna2 protein, mouse; D051663:Kv1.2 Potassium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C000654500:Scn2a protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels; D051662:Kv1.1 Potassium Channel