Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM.
Clustering of Na(+) channels at the nodes of Ranvier is coordinated by myelinating glia. In the peripheral nervous system, axoglial contact at the nodes is mediated by the binding of gliomedin and glial NrCAM to axonal neurofascin 186 (NF186). This interaction is crucial for the initial clustering of Na(+) channels at heminodes. As a result, it is not clear whether continued axon-glial contact at nodes of Ranvier is required to maintain these channels at the nodal axolemma. Here, we report that, in contrast to mice that lack either gliomedin or NrCAM, absence of both molecules (and hence the glial clustering signal) resulted in a gradual loss of Na(+) channels and other axonal components from the nodes, the formation of binary nodes, and dysregulation of nodal gap length. Therefore, these mice exhibit neurological abnormalities and slower nerve conduction. Disintegration of the nodes occurred in an orderly manner, starting with the disappearance of neurofascin 186, followed by the loss of Na(+) channels and ankyrin G, and then βIV spectrin, a sequence that reflects the assembly of nodes during development. Finally, the absence of gliomedin and NrCAM led to the invasion of the outermost layer of the Schwann cell membrane beyond the nodal area and the formation of paranodal-like junctions at the nodal gap. Our results reveal that axon-glial contact mediated by gliomedin, NrCAM, and NF186 not only plays a role in Na(+) channel clustering during development, but also contributes to the long-term maintenance of Na(+) channels at nodes of Ranvier.
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; W.M. Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, New Jersey 08854; and Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016.
Veronique
V
Amor
Konstantin
K
Feinberg
Yael
Y
Eshed-Eisenbach
Anya
A
Vainshtein
Shahar
S
Frechter
Martin
M
Grumet
Jack
J
Rosenbluth
Elior
E
Peles
D000200:Action Potentials; D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D021381:Protein Transport; D011901:Ranvier's Nodes / Q000378:metabolism* / Q000502:physiology; D013049:Spectrin / Q000378:metabolism; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
D017487:Ankyrins; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D009414:Nerve Growth Factors; C504593:Nfasc protein, mouse; C491151:Nrcam protein, mouse; D061566:Voltage-Gated Sodium Channels; C520020:gliomedin protein, mouse; D013049:Spectrin
NrCAM; Schwann; gliomedin; myelin; neurofascin; node of Ranvier