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The Nodes of Ranvier: Molecular Assembly and Maintenance

Matthew N. Rasband1 and Elior Peles2

1Department of , Baylor College of Medicine, Houston, Texas 77030 2Department of Molecular Biology, The Weizmann Institute of Science, Rehovot 76100, Israel Correspondence: [email protected]; [email protected]

Action potential (AP) propagation in myelinated requires clustered voltage gated sodium and potassium channels. These channels must be specifically localized to nodes of Ranvier where the AP is regenerated. Several mechanisms have evolved to facilitate and ensure the correct assembly and stabilization of these essential axonal domains. This review highlights the current understanding of the intrinsic and glial extrinsic mechanisms that control the formation and maintenance of the nodes of Ranvier in both the peripheral (PNS) and (CNS).

xons conduct electrical signals, called action with high AP conduction velocities, low Apotentials (APs), among in a cir- metabolic demands, and reduced space require- cuit in response to sensory input, and between ments as compared with unmyelinated axons. motor neurons and muscles. In mammals and Thus, and the clustering of ion channels other , many axons are myelinated. in axons permitted the evolution of the complex Myelin, made by Schwann cells and oligoden- nervous systems found in vertebrates. This re- drocytes in the peripheral nervous system view highlights the current understanding of (PNS) and central nervous system (CNS), re- the axonal intrinsic and glial extrinsic mecha- spectively, is a multilamellar sheet of glial mem- nisms that control the formation and mainte- brane that wraps around axons to increase trans- nance of the nodes of Ranvier in both the PNS membrane resistance and decrease membrane and CNS. capacitance. Although myelin is traditionally viewed as a passive contributor to nervous sys- tem function, it is now recognized that myeli- THE ORGANIZATION OF MYELINATED nating also play many active roles including AXONS regulation of axon diameter, axonal energy me- Morphology tabolism, and the clustering of ion channels at gaps in the myelin sheath called nodes of Myelinated axons are divided into distinct do- Ranvier. Together, the active and passive prop- mains including nodes of Ranvier, paranodal erties conferred on axons by myelin, result in axoglial junctions (PNJ), juxtaparanodes (JXP),

Editors: Ben A. Barres, Marc R. Freeman, and Beth Stevens Additional Perspectives on Glia available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a020495 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a020495

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M.N. Rasband and E. Peles

and internodes (Fig. 1). At PNS nodes of Ran- –axon units and even extends vier, microvilli emanate from the outer aspect through the nodal gap (Court et al. 2006). In of the Schwann cells that myelinate the flank- the nodal gap, glial processes are embedded ing internodes to contact the nodal in (ECM)–rich material (Berthold et al. 1983; Ichimura and Ellisman (termed the “cement disk” by Ranvier) that par- 1991). In contrast, myelinating oligodendro- ticipates in node formation and is thought to cytes in the CNS do not form nodal microvilli. serve as a cationic pool through the negative Instead, some nodes are contacted by perinod- charges of sulfated proteoglycan chains (Fig. al or 2A) (Bekku et al. 2010a; Susuki et al. 2013). No- (OPC) processes (Black and Waxman1988; Butt des of Ranvier are bordered by the PNJ, a spe- et al. 1994, 1999). Although microvilli in the cialized axoglial contact formed between the PNS contribute to Naþ channel clustering dur- axolemma and the paranodal loops of the mye- ing development, the functions of perinodal linating cells. Here, myelin lamellae split into and OPCs remain obscure. Another a series of cytoplasmic loops that are closely important difference between myelinated PNS apposed to the axon, being separated by a gap and CNS axons is that the latter lack a basal of only 2.5–3 nm. These loops spiral around lamina. PNS myelinated axons have a basal the axon to form septate-like junctions with lamina that completely surrounds individual the axon; these junctions constitute the largest

Dendrite AIS

Myelin

Schwann Perinodal microvilli astrocyte CNS PNS

Axon

IND JXP PNJNode PNJ JXP IND

Figure 1. Axonal domains along the myelinated axons. A containing the , branched , and a myelinated axon is shown. Axons are myelinated by Schwann cells in the peripheral nervous system (PNS) and in the central nervous system (CNS). Action potentials (APs) generated at the axon initial segment (AIS) travel down the axon and are regenerated at the nodes of Ranvier until reaching the terminals. The axonal membrane is divided into distinct domains. The internodes (INDs) (shown partially in the lower cartoon) comprise the majority of the axon and are located beneath the compact myelin sheath. The juxtaparanodes (JXP) are located at the end of the internodes. Near the nodes of Ranvier, the myelin sheath ends with a series of cytoplasmic loops (e.g., paranodal loops) that generate a specialized junction with the axon (paranodal junction [PNJ], often referred to as the axoglial junction). Bordered by the PNJ are the nodes of Ranvier, which are gaps between myelin segments. In the PNS, the nodal axolemma is contacted by microvilli that originate from the outer aspect of the myelinating Schwann cells, whereas, in the CNS, some nodes are contacted by a process from a perinodal astrocyte or oligodendrocyte progenitor cell (OPC). Insets show EM images of a longitudinal section through the node of Ranvier in the CNS (perinodal astrocyte in red, paranodes in brown, and axon in purple) and the PNS (axon in purple). The nodal gap is filled with highly charged extracellular matrix material (dots).

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The Nodes of Ranvier

A PNS node CNS node Dp/Utrn DG αβ

Syn ERM Pln NrCAM Hyaluronan Lam Gldn NrC

VcanV2 NrC Bcan Cntn NF186 NF186 NF186 NF186 Bral1 Nav KCNQ Nav KCNQ

GG GG βIV βIV Actin Actin

BCParanode Juxtaparanode

? Tag1 NF155

? Tag1 Adam22 Cntn Caspr2 Caspr Kv1 ? 4.1B 4.1B αII/βII αII/βII Psd93/95 Actin Actin

Figure 2. Molecular organizations of axonal subdomains. Simplified illustration showing some of the molecules and interactions involved in the nodal (A), paranodal (B), and juxtaparanodal (C) domains. PNS nodes are contacted by microvilli of Schwann cells. Dystroglycan (DG) is autocleaved into a and b chains, which remain associated. b-DG interacts with dystrophin (Dp) and utrophin (Utrn). A transmembrane form of NrCAM is present at the microvilli. Interaction of laminins (Lam) and perlecan (Pln) with a-DG requires proper glyco- sylation of a-DG (thin black lines). Pln and sydecans 3/4 (Syn) are modified by heparan sulfate side chains (green lines). The furin-shed gliomedin (Gldn) trimerizes and is associated with heparan sulfate through its amino-terminal region and collagen-like domain and interacts with NrCAM and NF186 through its olfacto- medin domain. G and bIV represent AnkG and bIV , respectively. In the CNS, the nodal ECM is enriched with shed NrCAM, but its cellular source is unknown. VcanV2 and Bcan interact with Bral1 and hyaluronan through their G1 globular domains and with NF186 through the G3 domains. The intervening regions of VcanV2 and Bcan are modified by chondroitin sulfate side chains (light blue lines). Contactin (Cntn) was found at CNS nodes, but only weakly at a few PNS nodes. The cytoplasmic partners of NF155 at the paranodal junction and ligands of Adam22 at the juxtaparanode are currently unknown. (From Chang et al. 2013; reprinted, with permission, from Elsevier Limited # 2013.)

known intercellular junction. In elec- axon, separating the electrical activity of nodal tron micrographs of longitudinal sections axolemma from internodal axolemma, and through the paranodal region, the junctions ap- functioning as a boundary to limit the lateral pear as a series of ladder-like densities (i.e., diffusion of axonal membrane (Rose- transverse bands or septa) that arise from the nbluth 2009). As detailed below, the PNJ plays axon and contact the glial membranes (Rose- essential roles in the formation and mainte- nbluth 2009). PNJ have diverse functions that nance of nodal and JXP membrane domains. include attachment of the myelin sheath to the The third specialized region in myelinated ax-

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M.N. Rasband and E. Peles

ons, the so-called JXP, is located beneath the and the rapid propagation of APs. The molec- compact myelin at the interface between the ular compositions of each domain and their PNJ and internode. This region is character- –protein interactions are described be- ized by clusters of intramembranous particles low (Fig. 2). in freeze–fracture replicas (Stolinski et al. 1981; Tao-Cheng and Rosenbluth 1984) thought to Nodes of Ranvier correspond to delayed rectifier Kþ channels (Chiu and Ritchie 1980). These channels may AP propagation depends on the rapid de- and stabilize conduction and help to maintain the repolarization of the axolemma; these actions internodal , especially during are performed by Naþ and Kþ channels clus- myelination and (Chiu and Rit- tered at nodes (Fig. 2A). However, nodes are not chie 1984; Wanget al. 1993; Vabnickand Shrager uniform in their composition. Like 1998; Rasband 2010). As described below, the with different ionotropic neurotrans- formation of this domain depends on the pres- mitter receptors, nodes of Ranvier can also have ence of an intact PNJ. Finally, the internodal ax- one or more different kinds of voltage-gated olemma located beneath the compact myelin is Naþ and Kþ channels, although this diversity also considered a unique domain because there is relatively limited. For example, nodes can in- are distinct membrane proteins and structures clude Nav1.1, Nav1.2, Nav1.6, Nav1.7, Nav1.8, that comprise this region. In the PNS, the orga- and Nav1.9 (Fjell et al. 2000; Boiko et al. 2001; nization of the internodal axolemma is dictated Henry et al. 2005; Duflocq et al. 2008; Black et by the overlying myelin sheath. Here the mem- al. 2012). These Naþ channels function as the brane contains two linear rows of juxtaparano- pore-forming protein subunits that mediate ion dal-type intramembranous particles that flank a flux across the membrane. Naþ channels also paranodal-type aggregate at the inner mesaxon interact with the accessory b-subunits Navb1, and under the Schmidt–Lanterman incisures Navb2, and Navb4 (Chen et al. 2002, 2004; Buf- (Miller and Pinto da Silva 1977; Stolinski et al. fington and Rasband 2013). The b-subunits are 1985). However, in contrast to the PNJ, no dis- covalently linked to Naþ channels through an tinct junctional specialization (like transverse extracellular disulfide bond (Chen et al. 2012; bands) is present between the axolemma and Buffington and Rasband 2013) to promote the the adaxonal Schwann at the in- surface expression of Naþ channels and change ner mesaxon. Similar to the JXP, the aggregates their biophysical properties. In addition to Naþ found at the juxtamesaxonal (JXM) and juxta- channels, nodes of Ranvier are also enriched incisural lines correspond to delayed rectifier Kþ in Kþ channels (Cooper 2011). These include channels (Arroyo et al. 1999). Hence, the radial Kv3.1b, KCNQ2, and KCNQ3 (Devaux et al. organization of paranodal and juxtaparanodal 2003, 2004), which together regulate neuronal components along the internodes corresponds excitability (Battefeld et al. 2014; King et al. to the longitudinal (i.e., axial) polarity of these 2014). These channels have unique physiologies proteins near the nodes of Ranvier. In contrast to and together with the diversity of Naþ channels the PNS, no juxtamesaxonal organization is de- and their accessory subunits emphasize that not tected in the CNS (Arroyo et al. 2001). all nodes are created equal. Besides ion channels, nodes of Ranvier are also enriched with the cytoskeletal and scaffold- Composition ing proteins G (ankG) and bIV spectrin The molecular composition of the nodes, para- that together link the Naþ and Kþ channels to nodes, JXPs, and internodes is a remarkable ex- the underlying cytoskeleton (Kordeli et al. 1995; ample of reciprocal neuron–glia interactions Berghs et al. 2000). These scaffolds also link ion mediated by ECM proteins, cell adhesion mol- channelstoextrinsic(glial)interactionsthrough ecules (CAMs), and cytoskeletal scaffolds, all CAMs: the 186-kDa isoform of neurofascin designed to facilitate ion-channel clustering (NF186) and NrCAM (Davis et al. 1996). Nodal

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The Nodes of Ranvier

CAMs interact with a diverse and rich extracel- Kv1.1, Kv1.2, Kv1.4, and KVb2 subunits (Fig. lular matrix. In the PNS, nodal ECM proteins 2C) (Rasband et al. 2001). Intriguingly, at JXP include gliomedin, syndecans, laminins, NG2, there is also a CAM interaction homologous to and versican. A specialized ECM also exists in that found at paranodes. GPI-anchored TAG-1 the CNS and consists of the chondroitin sulfate (also known as contactin-2) and Caspr2 form a proteoglycans brevican, versican, neurocan, and complex and both are required for proper clus- phosphacan, as well as tenascin-R, Bral1, and tering of JXP Kv1 channels (Poliak et al. 2003). shed NrCAM (Susuki et al. 2013). Gliomedin, Proteomics of JXP Kv1 channels also revealed shed NrCAM, versican, brevican, and Bral1 are ADAM22 at JXP (Ogawa et al. 2010). Caspr2, all direct binding partners of NF186 (Eshed et al. Kv1 channels, and ADAM22 all have canonical 2005; Susuki et al. 2013). The aforementioned PDZ-binding motifs. Consistent with this fact, nodal microvilli in the PNS are also specifically the PDZ-domain proteins PSD95 and PSD93 enriched with unique proteins including ezrin, are also enriched at JXPs, although they are dis- radixin, moesin, EBP50, dystrophin, and utro- pensable for assembly of the Caspr2/TAG-1/ phin (Occhi et al. 2005). In contrast, no specific Kv1 channel complex (Horresh et al. 2008), proteins have been identified at the terminals of but loss of ADAM22 blocks the clustering of perinodal glial processes in the CNS. PSD95/93 without affecting Kv1 channel clus- tering (Ogawa et al. 2010). Thus, the functions of ADAM22 and PSD95/93 remain unknown. Paranodal Junctions Despite the clear dependence of Kv1 channel PNJ flank nodes of Ranvier and consist of a het- clustering on Caspr2 and TAG-1, how these erotrimeric CAM complex consisting of the gli- ion channels interact with Caspr2 and TAG-1, al, 155-kDa isoform of neurofascin (NF155) and and how ADAM22 is recruited to JXP domains an axonal complex of the glycosylphosphatidyl- remains unknown. inositol (GPI) anchored contactin and Caspr (Fig. 2B) (Charles et al. 2002). These proteins Internodes are all essential for the generation of the charac- teristic septate-like junction at the paranodes As described above, the PNS internode has athin (Bhat et al. 2001; Boyle et al. 2001; Gollan et al. line of alternating JXP–PNJ–JXP proteins that 2002; Rosenbluth 2009). Furthermore, the sig- followsthe spiral of the inner-mesaxon along the nificance of proper paranodal junctions in hu- internode (hence, termed the internodal me- man health can be seen in the recent identifica- saxonal line). These contact sites between the tion of human frameshift mutations in Caspr. myelin sheath and the axon share molecular fea- These mutations caused severe arthrogyposis tures of the JXP and PNJ. Furthermore, the PNS multiplex congenita, characterized by congeni- internode is enriched in CAMs of the Cadm tal joint contractures. These patients also had (also known as the Necl and SynCAM) family significantly reduced conduction of proteins (Maurel et al. 2007; Spiegel et al. velocities (Laquerriere et al. 2014). A specialized 2007). Specifically, internodal axolemma is en- cytoskeleton is also found at paranodesthat con- riched in Cadm3 and Cadm2, which forms a sists of ankyrinB, aII spectrin, bII spectrin, and ligand pair with internodal Cadm4 found on protein 4.1B (Ogawa et al. 2006). This paranodal the adaxonal surface of Schwann cells and oligo- cytoskeletal complex plays important roles in dendrocytes (Maurel et al. 2007; Spiegel et al. regulating the barrier functions of paranodes 2007; N Golan, Y Eshed, and E Peles, unpubl.). (see below). In the PNS, axon–glial interaction mediated by glial Cadm4 is required for the organization of the axonal membrane, accurate positioning of Juxtaparanodes Caspr at the paranodal area, as well as the clus- JXP are characterized mainly by the high-den- tering of Kv1 channels at the juxtaparanodal re- sity clustering of Kv1 Kþ channels consisting of gion and the internodal mesaxonal line (Golan

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M.N. Rasband and E. Peles

et al. 2013). The presence of Kv1 channels at the increases 1000-fold following phosphorylation mesaxonal line also depends on the presence of of the ankG-binding motif by the protein kinase the cytoskeletal adaptor protein 4.1G, which as- CK2 (also enriched at nodes) (Bre´chet et al. sociates with Cadm4 in Schwann cells (Ivano- 2008). Remarkably, a nearly identical ankyrin- vich et al. 2012). binding motif is found in KCNQ2/Q3 Kþ chan- Taken together, a picture emerges of a high- nels and likely evolved by convergent molecular ly organized distribution evolution to facilitate efficient node of Ranvier found along myelinated axons that uses com- function (Hill et al. 2008). Clustering of bIV mon kinds of protein complexes important for spectrin at nodes depends on its 15th spectrin domain assembly and/or function (see Table 1 repeat, which functions as its ankG-binding do- in Eshed-Eisenbach and Peles 2013 for a list of main (Yang et al. 2007), and mutation of bIV nodal components). In the next section, we will spectrin leads to disrupted nodes, ataxia, and discuss how these different types of proteins premature death (Yang et al. 2004). Silencing interact to organize the myelinated axon into expression of ankG in myelinating DRG-neu- discrete domains. ron/Schwann cell cocultures blocked the clus- tering of Naþ channels (Dzhashiashvili et al. 2007). Together, these observations emphasize ASSEMBLY OF THE NODES the importanceof intrinsiccytoskeletal and scaf- OF RANVIER folding protein interactions for proper node as- Formation of the nodes of Ranvier depends sembly and function. on both axonal–intrinsic and glial–extrinsic mechanisms. The assembly of nodes is orches- Extrinsic Regulators of Node Formation trated through the placement of several cyto- skeletal and tethering proteins along the axo- Freeze fracture electron microscopy (EM) stud- lemma at locations that are determined by the ies show developmental and cell contact medi- contacting oligodendrocytes and myelinating ated changes in the axolemma (Tao-Cheng and Schwann cells. Rosenbluth 1983). More recent studies revealed dynamic changes in the pattern of both Naþ and Kþ channel clustering during development and Intrinsic Regulators of Node Formation after demyelination (Dugandzija-Novakovic et In neurons, ankG is required for Naþ channel al. 1995; Rasband et al. 1998; Vabnick et al. clustering at the axon initial segment (AIS), 1999). During PNS nerve development, differ- which is structurally and functionally similar ent nodal domains follow a stereotypical se- to nodes, although its assembly is indepen- quence of events. Naþ channels are first clustered dent of extrinsic mechanisms (Rasband 2010). at the nodes, followed by the generation of the Because nodal Naþ and Kþ channels, NF186, paranodal junction and only then by the clus- NrCAM, and bIV spectrin all have ankyrin-bind- tering of Kþ channels at the juxtaparanodal re- ing motifs, ankG has been assumed to function gion (Vabnick et al. 1996, 1999; Schafer et al. at the center of node assembly as a master “pro- 2006). In the CNS, Naþ channel clustering fol- tein accumulator.” What evidence supports lows formation of paranodes (Rasband et al. this conclusion? Mutation of the ankG-binding 1999). In both the CNS and the PNS, Naþ chan- domain in NF186 blocks its ability to cluster at nels cluster initially at sites adjacent to the edges nodes (Susuki et al. 2013), and the ankG-bind- of processes extended byoligodendrocytes (Ras- ing domain in Naþ channels is both necessary band et al. 1999; Susuki et al. 2013) and myeli- and sufficient for channel localization. Chime- nating Schwann cells (Vabnicket al. 1996; Ching ras between the Naþ channel’s ankG-binding et al. 1999). Further longitudinal growth of these motif and an unrelated processescauses displacement of the clusters un- can cause it to cluster at nodes (Gasser et al. til ultimately two neighboring clusters appear to 2012). The affinity of ankG for Naþ channels fuse, thus forming a new node of Ranvier. These

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The Nodes of Ranvier

results indicate that these Naþ channel clusters Nodal Axoglial Interactions are positioned by direct glial cell contact. In agreement, Naþ channels are diffuse along ret- PNS nodes (Fig. 2A). During PNS myelination, inal cell axons until they cross the lam- heminodal clustering of Nav channels, that is inacribrosa and become myelinated, after which their accumulation at the edges of a growing they are clustered at nodes (Boiko et al. 2001). myelin segment, depends on the interaction of Naþ channels are not clustered after ablation axonal NF186 with glial gliomedin and NrCAM of oligodendrocytes (Mathis et al. 2001) or (Fig. 3A) (Eshed et al. 2005; Feinberg et al. Schwann cells (Vabnick et al. 1997) and are 2010). Gliomedin binds to NrCAM present on dispersed after demyelination (Dugandzija-No- the microvillar membrane, and also associates vakovic et al. 1995). Furthermore, nodal Naþ with other nodal ECM components to create channels are associated with the edges of mye- high avidity CAM-binding multimolecular linating Schwann cells in nerves that display complexes that drive the accumulation of shorter internodes as a result of remyelination NF186 in the underlying axolemma (Eshed (Dugandzija-Novakovic et al. 1995), or geneti- et al. 2007; Feinberg et al. 2010). As a binding cally impaired myelination (Koszowski et al. partner for NF186, ankG is recruited to the 1998). These results strongly support the idea NF186 complexes, followed by bIV spectrin that axoglial interactions induce the clustering and Naþ channels (Lambert et al. 1997; Eshed of Naþ channels at the node of Ranvier. As de- et al. 2005; Dzhashiashvili et al. 2007; Yanget al. tailed below, two distinct axoglial contact sites at 2007). The initial accumulation of NF186 at the nodes and the paranodes control the molec- heminodes as well as its internodal clearance ular assembly of the nodes of Ranvier. requires its extracellular domain, whereas its

A Heminodal clustering

B

Paranodal C restriction

Figure 3. The formation of PNS nodes of Ranvier. (A)Naþ channels (red circle) are trapped at heminodes that are contacted by Schwann cell microvilli ([MV] orange). Axon–glia interaction at this site is mediated by binding of gliomedin and glial NrCAM to axonal NF186. A transmembrane form of glial NrCAM traps gliomedin on Schwann cell microvilli and enhances its binding to axonal NF186. (B) The distribution of Naþ channels is restricted between two forming myelin segments by the PNJ (blue). Three CAMs, NF155 present at the glial paranodal loops, and an axonal complex of Caspr and contactin mediate axon–glia interaction and the formation of the PNJ. (C) These two extrinsic cooperating mechanisms provide reciprocal backup systems and ensure that Naþ channels are found at high density at the nodes. Finally, the entire nodal complex requires stabilization and interaction with cytoskeletal and scaffolding proteins, which constitute a third, intrinsic mechanism for Naþ channel clustering. (From Feinberg et al. 2010; reprinted, with permission, from Elsevier Limited # 2010.)

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M.N. Rasband and E. Peles

stabilization in mature nodes requires its cyto- targeting to the axolemma is ankG-dependent, plasmic ankG-binding domain (Zhang et al. but gliomedin-induced CAM clustering re- 2012). NF186 binds both ankG (Garver et al. quires a mobile surface pool of CAMs. 1997) and ECM proteins (Eshed et al. 2005; Sus- CNS nodes (Fig. 2A). As in the PNS, specific uki et al. 2013), and, thus, plays a key role during glial-extrinsic mechanisms contribute to CNS nodeformation in bothCNSandPNS (Sherman node of Ranvier formation (Fig. 2A). One of etal.2005;Zontaetal.2008;Thaxtonetal.2011). the first studies to investigate how Naþ channels In the PNS, secretion of gliomedin into the nod- are clustered in CNS axons concluded that a al gap and its accumulation on microvilli by soluble factor secreted by oligodendrocytes pro- binding to NrCAM initiates the molecular as- motes Naþ channel clustering (Kaplan et al. sembly of the nodes of Ranvier (Feinberg et al. 1997). However, other evidence suggested that 2010). Different binding sites for gliomedin and contact by oligodendrocytes intiates node for- NrCAMon NF186 allow the multimolecular gli- mation (Rasband et al. 1999). In contrast to the al complexes to cluster axonal NF186 at hemin- PNS, in which contact-dependent mechanisms odes rapidly and efficiently (Labasque et al. are necessary to assemble nodes (see above), a 2011). By genetically eliminating the expression combination of both contact-dependent inter- of different combinationsof nodal andparanod- actions and secreted factors participate in CNS al CAMs, it was shown that Schwann cells gov- node formation (Susuki et al. 2013). Further- ern the assembly of nodes of Ranvier by two dis- more, the sequence of contact-dependent events tinct contact-dependent mechanisms: (1) active in the CNS is distinct from that in the PNS. First, clustering of Naþ channels at heminodes (Fig. myelination begins in the CNS together with 3A), and (2) restricting Naþ channel distribu- the formation of the PNJ (Rasband et al. 1999; tion to the nodal gap (Fig. 3B) (Feinberg et al. Susuki et al. 2013). As described above, the 2010). The first mechanism of heminodal clus- PNJ functions as a barrier to restrict membrane tering requires gliomedin, the glial form of proteins between the adjacent myelin segments. NrCAM, and axonal NF186. The second coop- Thus, the initiating event in CNS node for- erating mechanism that allowsthe accumulation mation is the axoglial interactions that occur of ion channels at mature nodes occurs indepen- at the PNJ. After PNJ assembly, Naþ channels dently of these axonodal CAMs and depends on accumulate at the edges of the nascent myelin the formation of the paranodal junction (see be- sheath together with NF186, ankG, and bIV low). These two cooperating processes provide spectrin (Susuki et al. 2013). The nodal ECM reciprocal backup systems to ensure that Naþ proteins, although sufficient to induce cluster- channels are clustered at nodes in the PNS (Fein- ing of nodal proteins alone, then bind to NF186 berg et al. 2010). and likely stabilize the entire nodal protein com- How do different components reach PNS plex rather than initiate its assembly. Together, nodes of Ranvier? In general, targeting proteins although some of the ECM proteins are unique to specific membrane domains is achieved ei- to the CNS, these observations reveal two ex- ther by selective transport, or random transport trinsic, glial mechanisms for ion channel clus- followed by specific retention in the correct do- tering similar to the PNS: the primary PNJ-bar- main or removal of mislocalized proteins. Re- rier mechanism, and a secondary NF186-ECM tention can be accomplished by anchoring to mechanism. These two mechanisms work in large molecular scaffolds or by restricting later- concert with the intrinsic ankG-bIV spectrin al diffusion (Jensen et al. 2011; Lasiecka and clustering mechanism described above. The Winckler 2011). At PNS nodes during develop- idea that multiple independent, yet overlap- ment CAMs are clustered from a cell surface ping, processes contribute to CNS node of Ran- pool, whereas the accumulation of Naþ chan- vier formation was tested by generating mice, nels and ankG requires vesicular transport from in which two of these overlapping mechanisms the cell soma (Zhang et al. 2012). These results were disrupted simultaneously (Susuki et al. are consistent with the model that Naþ channel 2013). This was necessary because loss of only

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The Nodes of Ranvier

a single mechanism (e.g., PNJ, ECM, or cyto- PNJ domains can influence how mem- skeleton) results in mild impairments of chan- brane proteins partition among nodal, PNJ, nel clustering rather than overt loss. If multiple and JXP membrane domains. Indeed, mutants mechanisms contribute to CNS node forma- lacking myelin have paranodal abnor- tion, we reasoned that loss of a single one might malities and impaired paranodal barriers with not disrupt node formation, and that the two Kv1 Kþ channels found in paranodal domains remaining mechanisms could compensate to (Dupree et al. 1999; Ishibashi et al. 2002). Sec- cluster Naþ channels. We further reasoned that ond, the paranodal CAMs assemble a special- loss of two mechanisms might cause profound ized paranodal cytoskeleton consisting of pro- disruption of nodes if the remaining mecha- tein 4.1B, aII spectrin, and bII spectrin (Ogawa nism cannot completely rescue nodes. It was et al. 2006; Horresh et al. 2010). Previous studies found that mice with two mechanisms disrupt- of how AIS form revealed the existence of an ed at once had profound disruptions in CNS intraxonal boundary, or barrier, consisting of node of Ranvier formation, impaired nerve aII spectrin, bII spectrin, and ankyrinB that conduction, and early lethality compared with functioned to restrict ankG and bIV spectrin wild-type mice or mice lacking just a single clus- to the proximal axon (Galiano et al. 2012). tering mechanism (Susuki et al. 2013). Taken Loss of the boundary permitted ankG to extend together, these observations support the con- into the distal axon. Because paranodes share clusion that three mechanisms work together many of these same proteins, it was proposed to assemble CNS nodes of Ranvier. that the paranodal cytoskeleton may also func- tion as a repeating boundary to restrict mem- brane proteins (i.e., ion channels) to JXP and CAM-Mediated Formation of a Cytoskeletal nodes. This possibility was directly tested using Barrier at the Paranodal Junction mice that lacked paranodal bII spectrin or para- The ECM and cytoskeletal mechanisms de- nodal 4.1B. In bII spectrin mutant mice, al- scribed above work through ankG. This is con- though the paranodal CAMs remained at para- sistent with the observation that the ankG- nodes, and PNJ still had transverse bands, binding domain in Naþ channels is both neces- Kv1 Kþ channels were no longer restricted to sary and sufficient for nodal Naþ channel clus- JXP domains (Zhang et al. 2013). Thus, para- tering (Gasser et al. 2012). But how do PNJ nodal CAMs, their specialized lipid environ- function to restrict axonal membrane proteins ments, and transverse bands are not sufficient to distinct domains (Fig. 3B)? Loss of Caspr, to form paranodal barriers. Instead, the para- contactin, or NF155 all result in disrupted par- nodal submembranous cytoskeleton constitutes anodes with absence of transverse bands. Al- the paranodal cytoskeletal barrier. In further though these paranodal mutants still have clus- support of this, the interaction between Caspr tered Naþ channels (caused by the redundant and protein 4.1B at paranodes has been shown ECM/NF186 and cytoskeletal mechanisms), to be important for the generation of a robust they fail to exclude JXP proteins from PNJ do- paranodal membrane barrier (Horresh et al. mains. Thus, paranodal CAMs are essential for 2010). the barrier function of the PNJ. How do these CAMs restrict JXP proteins from paranodes? MAINTAINING EXCITABLE DOMAINS Two mechanisms have been proposed. First, as IN MYELINATED AXONS the PNJ develops, the CAMs that define this domain acquire biochemical properties consis- The interactions of the nodal complex with cy- tent with -associated proteins (Schafer toskeletal and ECM components, as well as the et al. 2004). Thus, the lipid membrane environ- formation of the paranodal barrier, all play a ments flanking each node of Ranvier are unique role in both assembly and maintenance of the from those found at nodes and JXP domains, nodes. NF186 is dispensable for the assembly and the unique biochemical properties of these of AIS and nodes (Hedstrom et al. 2007; Zonta

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M.N. Rasband and E. Peles

et al. 2008; Feinberg et al. 2010), but is critical Some candidates include the adhesion receptor for the maintenance of the AIS (Zonta et al. dystroglycan(Saitoetal.2003;Occhietal.2005), 2011), as well as of nodes in the PNS (Zhang the heparan sulfate proteoglycans (HSPGs) syn- et al. 2012) and the CNS (Desmazieres et al. decan 3, syndecan 4 (Goutebroze et al. 2003; 2014). Interestingly, CNS nodes are more sus- Melendez-Vasquez et al. 2005), and perlecan ceptible to disruption after genetic deletion of (Bangratz et al. 2012), the ECM components NF186 in adult mice than PNS nodes, an obser- collagen XXVIII (Grimal et al. 2010) and colla- vation that likely reflects the major contribu- gen V (Melendez-Vasquez et al. 2005), and the tion of the PNJ in the CNS. In the PNS, removal gliomedin-related protein myocilin (Kwon et al. of gliomedin and NrCAM, and hence the glial 2013). Gliomedin binds HSPGs (Eshed et al. clustering signal operating through NF186, re- 2007), and this interaction could further con- sulted in gradual loss of Naþ channels and other tribute to nodal stabilization, similar to the axonal components that form the nodes (Amor role HSPGs play in CNS nodes (Dours-Zim- et al. 2014). These results revealed that contin- merman et al. 2009; Bekku et al. 2010b; Susuki uous axon–glia interaction mediated by these et al. 2013). molecules is required for long-term mainte- Given their significant role in node assem- nance of Naþ channels at nodes of Ranvier bly, it is not surprising that the PNJs are also (Amor et al. 2014). In the CNS, perinodal ECM required for node maintenance. Thus, in mu- components accumulate after Naþ channels are tant mice with paranodal abnormalities, such as clustered and, thus, likely play a stabilizing role mice lacking Caspr (Rios et al. 2003), the ga- (Susuki et al. 2013). This highly variable and lactolipids galactocerebroside (GalC) and sulfa- redundant ECM always contains BralI, which tide (Dupree et al. 1998; Rosenbluth et al. 2003), is a -specific link protein that stabilizes or NF155 (Pillai et al. 2009) nodes, gradually the binding of lecticans and hyaluronic acid become larger and more irregular in shape. Al- (Cicanic et al. 2012). In BralI knockout mice, though the paranodal junction-dependent bar- changes in the nodal ECM (i.e., brevican, versi- rier forms in PNS nodes, this mechanism is not canV2, and hyaluronan are missing) do not re- always sufficient to maintain Naþ channel clus- sult in changes in Naþ channel clustering at the ters at the axolemma in mature nodes. Inter- node. However, BralI mice show slower AP con- estingly, although the initial accumulation of duction (Bekku et al. 2010b), probably because NF186 at heminodes in the PNS requires its the BralI-associated ECM serves as an extracel- extracellular domain, its cytoplasmic ankyrin lular ion pool that facilitates nodal APs. Thus, G-binding domain mediates its transport and the nodal ECM, at least in the CNS, is crucial for stabilization in mature nodes, suggesting that maintaining functional nodes. Given the anal- additional mechanisms, likely involving ankG, ogy between CNS and PNS nodes, it is likely regulate nodal maintenance (Zhang et al. 2012). that, in addition to gliomedin and NrCM, other In addition, axon–glial interactions at nodes ECM components that bind NF186 are involved also control nodal stability and the organization in stabilization and maintenance of PNS nodes. by preventing the intrusion of the adjacent The involvement of other glial-derived ligands paranodal loops onto the nodal axolemma in preserving the nodal complex in the PNS is (Thaxton et al. 2011; Amor et al. 2014; Desma- an attractive idea in light of the observation zieres et al. 2014). Maintaining the exquisite that Naþ channels were still present in about molecular organization of myelinated axons, two-thirds of the nodes in adult mice lacking and particularly the nodal environ is of interest both gliomedin and NrCAM (Amor et al. 2014) given the presence of autoantibodies to nodal or NF186 (Desmazieres et al. 2014). The nodal CAMs in Guillain–Barre syndrome (GBS), gap in the PNS contains several proteins that chronic inflammatory demyelinating polyneu- could cooperate with gliomedin and NrCAM ropathy (CIDP), and (Mathey in maintaining the composition of the nodal et al. 2007; Pruss et al. 2011; Devaux 2012; De- axolemma (Eshed-Eisenbach and Peles 2013). vaux et al. 2012; Ng et al. 2012). The presence of

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The Nodes of Ranvier

such in animal models of these neu- National Institutes of Health, NINDS Grants ropathies leads to the disorganization of the (NS50220 to E.P., NS044916 to M.N.R., and nodes of Ranvier, formation of some binary no- NS069688 to M.N.R.), the Israel Science Foun- des, lengthening of the nodal gap, and reduced dation, the United States–Israel Binational Sci- nerve conduction (Lonigro and Devaux 2009). ence Foundation, the European Research Proj- In addition to the direct disruption of nodes by ects on Rare Diseases (E-Rare-2), the National autoimmune attack described above, loss of Multiple Sclerosis Society, and the Dr. Miriam the myelin sheath (e.g., stroke and and Sheldon G. Adelson Medical Research injury), dysmyelination (e.g., Charcot–Marie– Foundation. E.P.is the Incumbent of the Hanna Tooth disease), or hypomyelination (e.g., Peli- Hertz Professorial Chair for Multiple Sclerosis zaeus–Merzbacher disease) all include, as a and Neuroscience. common sequela, the aberrant clustering of Naþ andKþ channels.Furthermore,geneticstud- ies have identified mutations in ion channels REFERENCES (e.g., KCNQ2, Nav1.1, and Nav1.6), scaffolding Amor V, Feinberg K, Eshed-Eisenbach Y, Vainshtein A, proteins (e.g., ankG and aII spectrin), and Frechter S, Grumet M, Rosenbluth J, Peles E. 2014. þ CAMs (e.g., Casprand Caspr2), which are found Long-term maintenance of Na channels at nodes of Ranvier depends on glial contact mediated by gliomedin at and near nodes of Ranvier (for review, see and NrCAM. J Neurosci 34: 5089–5098. Faivre-Sarrailh and Devaux 2013 and Susuki Arroyo EJ, Xu YT, Zhou L, Messing A, Peles E, Chiu SY, 2013). Together, these observations emphasize Scherer SS. 1999. Myelinating Schwann cells determine the necessity of nodes for human health, and the internodal localization of Kv1.1, Kv1.2, Kvb2, and Caspr. J Neurocytol 28: 333–347. suggest the proper organization of nodes of Arroyo EJ, Xu T, Poliak S, Watson M, Peles E, Scherer SS. Ranvier and their associated domains is an es- 2001. Internodal specializations of myelinated axons in sential consideration for any therapeutic effort the central nervous system. Cell Tissue Res 305: 53–66. aimed at nervous system repair or preservation Bangratz M, Sarrazin N, Devaux J, Zambroni D, Echaniz- Laguna A, Rene´ F, Boe¨rio D, Davoine CS, Fontaine B, after disease or injury. Feltri ML, et al. 2012. A mouse model of Schwartz–Jam- pel syndrome reveals myelinating Schwann cell dysfunc- tion with persistent axonal in vitro and CONCLUDING REMARKS distal peripheral nerve hyperexcitability when perlecan is lacking. Am J Pathol 180: 2040–2055. In conclusion, the cellular and molecular mech- Battefeld A, Tran BT,Gavrilis J, Cooper EC, Kole MH. 2014. anisms that have evolved to facilitate the assem- Heteromeric Kv7.2/7.3 channels differentially regulate bly and maintenance of membrane domains initiation and conduction in neocortical myelinated axons. J Neurosci 34: 3719–3732. along myelinated axons provide exquisite exam- Bekku Y,Vargova L, GotoY,VorisekI,DmytrenkoL, Narasaki ples of how myelinating glia shape and influ- M, Ohtsuka A, Fassler R, Ninomiya Y, Sykova E, et al. ence the function and efficiency of neurons. Al- 2010a. Bral1: Its role in diffusion barrier formation and though a great deal is known about both the conductionvelocity intheCNS.JNeurosci30:3113–3123. Bekku Y,Vargova´ L, GotoY,Vorı´sek I,DmytrenkoL, Narasaki extrinsic and intrinsic mechanisms regulating M, Ohtsuka A, Fa¨ssler R, Ninomiya Y, Sykova´ E, et al. assembly and maintenance of nodes, para- 2010b. Bral1: Its role in diffusion barrier formation and nodes, and JXPs, much work remains to be per- conductionvelocity intheCNS.JNeurosci30:3113–3123. formed to have a full understanding of how Berghs S, Aggujaro D, Dirkx R, Maksimova E, Stabach P, Hermel JM, Zhang JP,Philbrick W,Slepnev V,Ort T,et al. these domains are assembled and maintained, 2000. bIV spectrin, a new spectrin localized at axon ini- and how to both preserve and repair these do- tial segments and nodes of Ranvier in the central and mains after injury. peripheral nervous system. J Cell Biol 151: 985–1002. Berthold CH, Nordborg C, Hildebrand C, Conradi S, Sourander P, Lugnegard H. 1983. Sural nerve biopsies from workers with a history of chronic exposure to or- ACKNOWLEDGMENTS ganic solvents and from normal control cases. Morpho- metric and ultrastructural studies. Acta Neuropathol 62: We thank Dr. Yael Eshed-Eisenbach for dis- 73–86. cussion and comments. Work performed in Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, St the authors’ laboratories is supported by the Martin M, Li J, Einheber S, Chesler M, Rosenbluth J, et

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The Nodes of Ranvier: Molecular Assembly and Maintenance

Matthew N. Rasband and Elior Peles

Cold Spring Harb Perspect Biol 2016; doi: 10.1101/cshperspect.a020495 originally published online September 9, 2015

Subject Collection Glia

The Nodes of Ranvier: Molecular Assembly and Oligodendrocyte Development and Plasticity Maintenance Dwight E. Bergles and William D. Richardson Matthew N. Rasband and Elior Peles in Health and Disease Oligodendrocytes: Myelination and Axonal Richard M. Ransohoff and Joseph El Khoury Support Mikael Simons and Klaus-Armin Nave The Astrocyte: Powerhouse and Recycling Center Drosophila Central Nervous System Glia Bruno Weber and L. Felipe Barros Marc R. Freeman Microglia Function in Central Nervous System Perisynaptic Schwann Cells at the Neuromuscular Development and Plasticity : Adaptable, Multitasking Glial Cells Dorothy P. Schafer and Beth Stevens Chien-Ping Ko and Richard Robitaille Transcriptional and Epigenetic Regulation of Astrocytes Control Synapse Formation, Function, Oligodendrocyte Development and Myelination in and Elimination the Central Nervous System Won-Suk Chung, Nicola J. Allen and Cagla Eroglu Ben Emery and Q. Richard Lu Origin of Microglia: Current Concepts and Past Schwann Cell Myelination Controversies James L. Salzer Florent Ginhoux and Marco Prinz Glia Disease and Repair−−Remyelination Schwann Cells: Development and Role in Nerve Robin J.M. Franklin and Steven A. Goldman Repair Kristján R. Jessen, Rhona Mirsky and Alison C. Lloyd Astrocytes in Neurodegenerative Disease Perineurial Glia Hemali Phatnani and Tom Maniatis Sarah Kucenas

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