TY - JOUR
T1 - Long-term maintenance of Na+ channels at nodes of ranvier depends on glial contact mediated by gliomedin and NrCAM
AU - Amor, Veronique
AU - Feinberg, Konstantin
AU - Eshed Eisenbach, Eisenbach, Yael
AU - Vainshtein, Anya
AU - Frechter, Shahar
AU - Grumet, Martin
AU - Rosenbluth, Jack
AU - Peles, Elior
N1 - National Institutes of Health [NS50220, NS037475]; Israel Science Foundation; Legacy Heritage Biomedical Fund; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; National Multiple Sclerosis Society [RG3618B9]This work was supported by the National Institutes of Health (Grant NS50220 to E.P. and Grant NS037475 to J.R.), the Israel Science Foundation, The Legacy Heritage Biomedical Fund, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the National Multiple Sclerosis Society (Grant RG3618B9 to J.R.). E.P. is the Incumbent of the Hanna Hertz Professorial Chair for Multiple Sclerosis and Neuroscience. We thank Peter Shrager for discussion and valuable advice, Matthew Rasband and Peter Brophy for antibodies, and Raffi Saka for mice maintenance.
PY - 2014
Y1 - 2014
N2 - 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+IV 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.
AB - 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+IV 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.
UR - http://www.scopus.com/inward/record.url?scp=84899480195&partnerID=8YFLogxK
U2 - https://doi.org/10.1523/JNEUROSCI.4752-13.2014
DO - https://doi.org/10.1523/JNEUROSCI.4752-13.2014
M3 - مقالة
SN - 0270-6474
VL - 34
SP - 5089
EP - 5098
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 15
ER -