Editing Node of Ranvier (section)

==Development==
===Myelination of nerve fibers===
The complex changes that the Schwann cell undergoes during the process of myelination of peripheral nerve fibers have been observed and studied by many.  The initial envelopment of the axon occurs without interruption along the entire extent of the Schwann cell.  This process is sequenced by the in-folding of the Schwann cell surface so that a double membrane of the opposing faces of the in-folded Schwann cell surface is formed.  This membrane stretches and spirally wraps itself over and over as the in-folding of the Schwann cell surface continues.  As a result, the increase in the thickness of the extension of the [[myelin]] sheath in its cross-sectional diameter is easily ascertained.  It is also evident that each of the consecutive turns of the spiral increases in size along the length of the axon as the number of turns increase.  However, it is not clear whether or not the increase in length of the myelin sheath can be accounted solely by the increase in length of axon covered by each successive turn of the spiral, as previously explained. 
At the junction of two Schwann cells along an axon, the directions of the lamellar overhang of the myelin endings are of opposite sense.<ref>{{cite journal | doi = 10.1083/jcb.3.4.589 |author1=Uzmman B. G. |author2=Nogueira-Graf G. | year = 1957 | title = Electron microscope studies of the formation of nodes of Ranvier in mouse sciatic nerves | journal = Journal of Biophysical and Biochemical Cytology | volume = 3 | issue = 4| pages = 589–597 | pmid = 13449102 | pmc = 2224104 }}</ref> This junction, adjacent of the Schwann cells, constitutes the region designated as the node of Ranvier.

===Early stages===
Researchers prove that in the developing CNS, [[Nav1.2]] is initially expressed at all forming nodes of Ranvier.<ref>{{cite journal | doi = 10.1016/S0896-6273(01)00265-3 | vauthors = Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS, etal | year = 2001 | title = Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon | journal = [[Neuron (journal)|Neuron]] | volume = 30 | issue = 1 | pages = 91–104 | pmid = 11343647 | s2cid = 7168889 | doi-access = free }}</ref> Upon maturation, nodal Nav1.2 is down-regulated and replaced by Nav1.6.  Nav1.2 is also expressed during PNS node formation, which suggests that the switching of Nav-channel subtypes is a general phenomenon in the CNS and PNS.  In this same investigation, it was shown that Nav1.6 and Nav1.2 colocalize at many nodes of Ranvier during early myelination.  This also led to the suggestion that early clusters of Nav1.2 and Nav1.6 channels are destined to later become nodes of Ranvier. [[Neurofascin]] is also reported to be one of the first proteins to accumulate at newly forming nodes of Ranvier.  They are also found to provide the nucleation site for attachment of ankyrin G, Nav channels, and other proteins.<ref>{{cite journal |vauthors=Lambert S, Davis JQ, Bennett V | year = 1997 | title = Morphogenesis of the node of Ranvier: co-clusters of ankyrin and ankyrin-binding integral proteins define early developmental intermediates | url= | journal = [[Journal of Neuroscience]] | volume = 17 | issue = 18| pages = 7025–7036 | pmid = 9278538 | pmc = 6573274 | doi=10.1523/JNEUROSCI.17-18-07025.1997}}</ref> The recent identification of the Schwann cell microvilli protein gliomedin as the likely binding partner of axonal neurofascin brings forward substantial evidence for the importance of this protein in recruiting Nav channels to the nodes of Ranvier.  Furthermore, ''Lambert et al.'' and ''Eshed et al.'' also indicates that neurofascin accumulates before Nav channels and is likely to have crucial roles in the earliest events associated with node of Ranvier formation.   Thus, multiple mechanisms may exist and work synergistically to facilitate clustering of Nav channels at nodes of Ranvier.

===Nodal formation===
The first event appears to be the accumulation of cell adhesion molecules such as NF186 or NrCAM.  The intra-cellular regions of these cell-adhesion molecules interact with ankyrin G, which serves as an anchor for sodium channels. In the PNS, this interaction has been elucidated. The Ig superfamily membrane protein NrCAM acts as a pioneer molecule in the formation of the nodes by recruiting ankyrin-G, a mediator protein in the connection of actin-spectrin cytoskeleton to the ion gated channels present at the node.<ref>{{cite journal |last1=Hill, Nishino, Nakajo |first1=AS, A, K |title=Ion channel clustering at the axon initial segment and node of Ranvier evolved sequentially in early chordates |journal=PLOS Genet |date=2008 |volume=4 |issue=12 |pages=e1000317 |doi=10.1371/journal.pgen.1000317 |doi-access=free |pmid=19112491 |pmc=2597720 }}</ref><ref>{{cite journal |last1=Lambert, Davis, Bennett |first1=S, JQ, V |title=Morphogenesis of the Node of Ranvier: Co-Clusters of Ankyrin and Ankyrin-Binding Integral Proteins Define Early Developmental Intermediates |journal=J Neurosci |date=1997 |volume=17 |issue=18 |pages=7025–7036 |doi=10.1523/JNEUROSCI.17-18-07025.1997 |pmid=9278538 |pmc=6573274 }}</ref> At the same time, the periaxonal extension of the glial cell wraps around the axon, giving rise to the paranodal regions.  This movement along the axon contributes significantly to the overall formation of the nodes of Ranvier by permitting heminodes formed at the edges of neighboring glial cells to fuse into complete nodes.
Septate-like junctions form at the paranodes with the enrichment of NF155 in glial paranodal loops.  
[[File:Nodes of Ranvier.png|thumb|Nodes of Ranvier in the Central and Peripheral Nervous Systems]]
Immediately following the early differentiation of the nodal and paranodal regions, potassium channels, Caspr2 and TAG1 accumulate in the juxta-paranodal regions. This accumulation coincides directly with the formation of compact myelin. In mature nodal regions, interactions with the intracellular proteins appear vital for the stability of all nodal regions.  In the CNS, [[oligodendrocytes]] do not possess microvilli, but appear capable to initiate the clustering of some axonal proteins through secreted factors.  The combined effects of such factors with the subsequent movements generated by the wrapping of oligodendrocyte periaxonal extension could account for the organization of CNS nodes of Ranvier.