molecular specializations at nodes and paranodes in peripheral nerve

MICROSCOPY RESEARCH AND TECHNIQUE 34:452-461 (1996)

Molecular Specializations at Nodes and Paranodes in Peripheral Nerve STEVEN S. SCHERER Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104

KEY WORDS Myelin, Incisures, Gap junctions, Tight junctions, Adherens junctions, Con- nexin32, Schwann cells, Cell adhesion molecules, Neuropathy

ABSTRACT In the peripheral nervous system, nodes of Ranvier are formed by interactions between myelinating Schwann cells and axons. Nodes have an intricate ultrastructure, and their molecular architecture is similarly complex. A growing list of molecules have been found that are selectively localized to different parts of the nodes. Neural cell adhesion molecule (N-CAM), L1/ Ng-CAM, and tenascidcytotactin are enriched in the nodal basal lamina; hyaluronic acid, versicanl hyaluronectin, N-CAM, Ll/Ng-CAM, tenascidcytotactin, and the ganglioside GM1 are enriched in the nodal gap; myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, connexin32, E-cadherin, actin, the gangliosides GQlb and GDlb, the potassium channel KV1.5, and alkaline phosphatase are enriched in the paranodal region of the Schwann cell; voltage-dependent sodium channels and the cytoskeletal proteins spectrin and ankyrin are enriched in the nodal axolemma. Many of these molecules are probably essential for the proper functioning and stability of nodes. 0 1996 Wiley-Liss, Inc.

INTRODUCTION The myelin sheath is a conspicuously specialized

structure, and is a unique and fundamental adaptation of both the central and the peripheral nervous system of vertebrates. Nodes of Ranvier (Ranvier, 1878) are periodic interruptions in the myelin sheaths and en- able saltatory conduction. "he anatomy of the node and paranodal region, including its development, as well as pathological changes, are discussed elsewhere in this volume. The purpose of this review is to discuss the molecular components of nodes, including their possible roles in the pathogenesis of certain neuropathies. In the discussion below, the node of Ranvier is considered to consist of the following: (1) the basal lamina, (2) the nodal gap, (3) the paranodal region, and (4) the axon. A schematic drawing of some of these structures is shown in Figure 1A.

BASAL LAMINA Every Schwann cell is surrounded by a basal lamina,

and at nodes, the basal lamina that surrounds one Schwann cell continues uninterrupted to the adjacent Schwann cell. The basal laminae of Schwann cells contain both the B1 and the B2 laminin chains, but not the A chain, which is replaced by merosin, a homologue of the A chain (Ehrig et al., 1990; Sanes et al., 1990). Schwann cell basal laminae also contain type IV collagen, entactinhidogen, fibronectin, as well as the heparan sulfate proteoglycans N-syndecan and glypican (Carey et al., 1992,1993; Chiu and KO, 1994; Eld- ridge et al., 1986; Lorimier et al., 1992; Tona et al., 1993). All of these molecules are found throughout the longitudinal extent of the basal laminae; none appear to be selectively localized to the nodal basal lamina. Other molecules that are selectively localized to nodes,

however, are a t least in part associated with the nodal basal lamina; these include neural cell adhesion molecule (N-CAM), Ll/Ng-CAM, and cytotactin/tenascin (Daniloff et al., 1989; Martini et al., 1990; Mege et al., 1992; Rieger et al., 1986). Whether any of these localized molecules serve an important function is unknown, but as all of them are cell adhesion molecules, it is plausible that they stabilize the nodal structure.

NODAL GAP The nodal gaplperinodal space is the space under the

basal lamina between the two adjacent Schwann cells. It contains nodal villi/microvilli, which are fine pro- cesses of Schwann cells, as well as nodal gap substance, which is extracellular matrix. As yet, no molecules have been found that uniquely characterize the nodal villi, whose membranes appear similar to those of internodal Schwann cells by freeze-fracture (Blanchard et al., 1985; Waxman and Black, 1987). Further, the nodal villi and internodal membrane have similar numbers of voltage-sensitive sodium channels (Devor et al., 1993; Ritchie et al., 1990). The nodal villi also appear to contain the cell adhesion molecule L1 1 Rieger et al., 1986).

It has been known for some time that the nodal gap substance can be selectively stained with methylene blue and a variety of metal salts (Hess and Young, 1952; Landon and Langley, 1971; Quick and Waxman, 1977). One of the molecules responsible for this staining is hyaluronic acid, as hyaluronidase treatment

Received February 13, 1995; accepted in revised form March 20, 1995. Address reprint requests to Steven S. Scherer M.D., Ph.D., Department of

Neurology, Room 460, Stemmler Hall, 36th Street and Hamilton Walk, The University of Pennsylvania Medical Center, Philadelphia, PA 19104.

Q 1996 WILEY-LISS, INC.

MOLECULAR SPECIALIZATIONS OF NODES 453

A \ / paranodes

Compact mvelin Non-compact mvelin

Fig. 1. Schematic view of a myelinating Schwann cell (A), and the major myelin-related proteins of the myelin sheath (B). The myelinating Schwann cell shown in A has been “unrolled to reveal the regions that form compact myelin, the incisures, and the paranodes. T w o rows of tight junctions are depicted as continuous lines; these form a circumferential belt and are also found in the incisures. Gap junctions are depicted as ovals; these are found between the rows of tight junctions The disposition of the myelin-related proteins in two

apposed membranes of compact and non-compact myelin is shown in B. In the PNS, compact myelin contains Po, PMP-22, and MBP; in the CNS, it contains PLP and MBP. In the PNS, the non-compact myelin of the paranodes and incisures contains MAG and Cx32. Note Po and MAG have extracellular immunoglobulin-like domains (semi-cir- cles), and that PMP-22, PLP, and Cx32 all have four transmembrane domains.

454 S.S. SCHERER

abolishes nodal staining by some kinds of metal salts (Landon and Langley, 1971). Hyaluronic acid and the hyaluronate-binding domain of versicanhyaluronectin (probably the same protein) have been localized to the nodal gap (Abood and Abul-Haj, 1956; Apostolski et al., 1994; Delpech et al., 19821, but the function of these molecules in the nodal gap is unknown.

The nodal gap is also stained by Griffonia simplicifolia-B4 isolectin and peanut agglutinin (PNA), which are lectins that recognize terminal a- and p-D-galactose, respectively (Apostolski et al., 1994; Corbo et al., 1993; Streit et al., 1985). The actual molecule that Griffonia simplicifolia-B4 isolectin recognizes in the nodal gap is unknown. PNA binds to terminal galacto- syl pl-3 N-acetylgalactosamine [Gal(pl-3)GalNAcl, an epitope that is found on many glycoproteins and some glycolipids, including the gangliosides GM1, asialo GM1, and GDlb (Latov, 1990). On Western blots of proteins from peripheral nerve, PNA binds to versicanl hyaluronectin, which has the Gal(p1-3)GalNAc epitope and is found in the nodal gap (Apostolski et al., 1994; Delpech et al., 1982). PNA also binds to asialo GM1, with substantially higher affinity than to GM1 (Momoi et al., 1982), but asialo GM1 has not been reported to be a component of peripheral nerve.

Depending on how peripheral nerve fibers are pre- pared for histology, cholera toxin has been reported to bind to the nodal gap (Ganser et al., 19831, to the paranode (Corbo et al., 1993), and to compact myelin (Corbo et al., 1993). Although cholera toxin is well known to bind GM1 (Fishman, 19821, it also binds GDlb (Bren- nan et al., 1988). Thus, the paranodal staining with cholera toxin could be due to GDlb, which is localized to the paranode (Kusunoki et al., 1993). What cholera toxin binds to in the nodal gap, however, is unknown. While the most likely target is GM1, a known component of peripheral nerve (Chou et al., 1985; Ogawa- Goto et al., 19921, GM1 has not yet been localized in nerve by immunohistochemistry (Kusunoki et al., 1993).

The presence of GM1 and GDlb at nodes may be relevant to the pathogenesis of some acquired neuropathies, as antibodies against these gangliosides may cause some kinds of acquired, demyelinating peripheral neuropathies. The first link of anti-GM1 antibodies to neuropathy was the report of Freddo et al. (1986), who described a patient with a lower motor neuron syndrome and an IgM K paraprotein that recognized GM1 and GDlb. This patient may have had multifocal motor neuropathy, which is a chronic, demyelinating neuropathy that selectively affects motor fibers, and that is frequently associated with elevated antibody titers against GM1 and GDlb (Chaudhry et al., 1993). Elevated antibody titers against GM1 and GDlb have also been reported in patients who have acute, acquired peripheral neuropathies, including Guillain-Barre syndrome and Chinese paralysis syndrome/acute motor axonal neuropathy (Kinsella et al., 1994; Kornberg et al., 1994; McKhann et al., 1993).

How anti-GM1 antibodies cause neuropathy is unknown. If the relevant antigen were a component of the myelin sheath and/or node, then antibody-mediated attack would be a plausible mechanism. Deposits of IgM

were found in the nodal gaps in a sural nerve biopsy from one patient who had an IgM anti-GM1 paraprotein (Santoro et al., 1990), and in the nodal gaps of rabbit peripheral nerve after immunization with GM1 (Thomas et al., 1991). Anti-GM1 paraproteins from patients label nodal gaps (Santoro et al., 1990; Thomas et al., 1991), but most anti-GM1 paraproteins recognize the Gal(p1-3)GalNAc epitope (Latov, 19901, which is shared by GM1, asialo-GM1, and GDlb, as well as several glycoproteins, including versican (see above) and oligodendrocyte-myelin glycoprotein (OMGP see below). All molecules with the Gal(p1-3)GalNAc epitope are potential targets of antibody-mediated attack in patients who have anti-GM1 paraproteins or elevated polyclonal titers against the Gal(p1-3)GalNAc epitope. Hence, it has been difficult to determine which, if any, of the molecules present in the myelin sheath and/or nodes that have the Gal(p1-3)GalNAc are the relevant target of the anti-GM1 antibodies in these patients.

PARANODAL REGION Before discussing the structure of the paranode, it is

important to consider the biology of the myelinating Schwann cells, as well as the structure and composition of the myelin sheath (see Fig. 1). Myelinating Schwann cells are highly differentiated, polarized cells. Their adaxonal surface apposes the axon that they myeli- nate, and their abaxonal surfaces apposes the basal lamina that surrounds them (Webster and Favilla, 1984). During development, myelinating Schwann cells differentiate from the pre-myelinating Schwann cells (Mirsky and Jessen, 1990; Webster and Favilla, 1984). Schwann cells that will form myelin sheaths first become associated with an axon in a 1:l manner, and begin expressing myelin-related genes (Martini, 1994). The differentiation of myelinating Schwann cells is accompanied by the expression of high levels of myelin-related proteins and glycolipids, and requires maintained axon-Schwann cell interactions (Mirsky and Jessen, 1990).

Proteins of Compact Myelin The myelin sheath is an extraordinary spiral of cell

membrane that repeatly encircles the axon, and can be considered to contain two domains, the compact myelin itself and the periodic interruptions within in it, the Schmidt-Lanterman incisures and paranodal regions (Fig. 1A). In the PNS, the main proteins that characterize compact myelin are Po, peripheral myelin protein 22 kD (PMP-22), and myelin basic protein (MBP); in the CNS, proteolipid protein (PLP) and MBP are the main proteins (Lemke, 1992). The structure of these proteins, as well as their disposition in the myelin sheath, are shown in Figure 1B. Po has an immunoglobulin-like domain and hence is thought to function as a cell adhesion molecule that stabilizes compact myelin (Lemke and Axel, 1985). The absence of Po causes dysmyelination (Giese et al., 19921, and point mutations in the Po gene cause dominantly inherited demyelinating neuropathy in humans (Chance and Plea- sure, 1993). PMP-22 has four transmembrane domains, and point mutations in PMP-22 cause dysmyelination in Trember mice and in humans (Chance and Pleasure,


1993; Suter et al., 1993). The duplication of the region of chromosome 17 that contains the PMP-22 gene causes the most common form of inherited demyelinating neuropathy in humans, Charcot-Marie-Tooth (CMT) diseasehereditary motor and sensory neuropathy (HMSN)IA (Lupski et al., 1991). The deletion of the same region of chromosome 17 causes hereditary neuropathy with liability to pressure palsies, which is a milder demyelinating neuropathy than CMTMMSNIA (Chance and Pleasure, 1993; Suter et al., 1993). Unlike Po and PMP-22, which are intrinsic membrane proteins, MBP is a cytoplasmic protein, and is the main component of the major dense line. Mutations of the MBP gene in shiuerer mice cause profound CNS dysmyelination, but have no overt effect on PNS myelin, even though the major dense line is missing (Lemke, 1992).

Proteins of Non-Compact Myelin The periodic interuptions in the myelin sheath, the

Schmidt-Lanterman incisures/clefts and paranodal regions, are characterized by similar ultrastructural features as well as molecular specializations, and together comprise the non-compact portion of the myelin sheath. Po, PMP-22, and MBP are not found in the incisures or paranodes (Lemke, 1992). While it was initially con- troversial, myelin-associated glycoprotein (MAG) is specifically localized to the incisures and paranodal regions of PNS myelin, although it is also found on the adaxonal surface of both CNS and PNS myelin sheaths (Trapp and Quarles, 1984). MAG is a transmembrane protein that has five extracellular immunoglobulin- like domains (Fig. 1B); these may stabilize apposed Schwann cell membranes at the incisures and paranodes, although no abnormalities in these structures were reported in mice that completely lack MAG (Li et al., 1994; Montag et al., 1994). (The localization of MAG in non-compact myelin is shown in Fig. 3).

OMGP, which was originally discovered as a myelin- related protein in the CNS (Mikol et al., 19901, is also found in paranodes in the PNS (Apostolski et al., 1994). As discussed above, OMGP has a Gal(pl9)GalNAc epitope, which is recognized by PNA and many so- called anti-GM1 antibodies (Apostolski et al., 1994; Mikol and Stefansson, 1988). OMGP also has a carbohydrate epitope that is recognized by the HNK-1 antibody (Mikol et al., 19901, which is that same epitope that is recognized by so-called anti-MAG antibodies (Latov, 1990).

Anti-MAG antibodies were so named after discover- ing that IgM paraproteins in some patients with neuropathy recognize a carbohydrate that is present on MAG (Braun et al., 1982). Subsequently, however, this same epitope has been found on other glycoproteins and glycolipids of PNS myelin, including OMGP, Po, PMP-22, sulfated glucuronyl paragloboside, and sulfated glucuronyl lactosaminyl paragloboside (Hammer et al., 1993; Latov, 1990). HNK-1 also recognizes several other, myelin-related molecules expressed by Schwann cells, including L1, N-CAM, and cytotactid tenascin (Martini, 1994). Thus, it is unclear which, if any, of these molecules may be involved in the patho-

genesis of neuropathy in patients who have an anti- MAG paraprotein.

Proteins of Junctional Specializations In the PNS, numerous electron microscopic studies

have found that both incisures and paranodes appear to have tight junctions, gap junctions, and adherendin- termediate junctions (Peters et al., 1991; Sandri et al., 1982; Thomas and Ochoa, 1984). Thus, myelinating Schwann cells have all of the components of junctional specializations found in other epithelia except for desmosomes (Farquhar and Palade, 1963; Friend and Gi- lula, 1972).

As depicted in Figure lA, two or more rows of tight junctions are typically found between apposed Schwann cell membranes around the circumference of myelinating Schwann cells, as well as in the incisures. While gap junctions are not evident in transmission electron microscopy of thin sections, in freeze-fracture analysis, gap junctions are found between the rows of tight junctions at the paranodes and incisures (Figs. lA, 2). One gap junction protein, connexin32 (Cx32), has been found in myelinating Schwann cells, and is localized to the paranodes and incisures (Bergoffen et al., 1993), as shown in Figure 5. Thus, it is likely that Cx32 participates in the formation of gap junctions at these locations. These gap junctions probably play a critical role in the normal physiology of myelinating Schwann cells, as mutations in Cx32 cause the X-linked form CMT/HMSN (Bergoffen et al., 1993; Fairweather et al., 1994). Why other tissues that express comparable or even higher levels of Cx32 are not affected in CMTX patients is unknown (Bergoffen et al., 1993). As there are multiple connexin genes, one appealing possibility is that most tissues express more than one connexin (Bennett et al., 1991; Dermietzel et al., 1990; Haefliger et al., 1992; Willecke et al., 1991), so that the loss of Cx32 alone in these tissues is not deleterious. Myelinating Schwann cells, on the other hand, may express only Cx32 (Scherer, unpublished observation), thereby rendering them selectively vul- nerable to Cx32 mutations.

Adherens junctions are located between the apposed adjacent layers of Schwann cell membrane at incisures and paranodes (Peters et al., 1991; Sandri et al., 1982; Thomas and Ochoa, 1984). While they are frequently referred to as being desmosome-like, they lack the ultrastructural features of true desmosomes, such as tonofilaments (Garrod, 1993). Rather, they appear similar to adherenslintermediate junctions of other epithelia (Boller et al., 1985; Nagafuchi et al., 1993). E-cadherin is a component of adherens junctions but not of desmosomes (Boller et al., 19851, and has just been localized to adherens junctions of myelinating Schwann cells at both the incisures and the paranodes (Fig. 4; Fannon et al., 1995). As E-cadherin is a calcium-dependent cell adhesion molecule, its probable function is to bind adjacent layers of Schwann cells at the paranodes and incisures. Such a role fits the observation that low- ering the extracellular level of calcium, which inhibits the binding of cadherins (Takeichi, 19901, drastically affects the integrity of the paranodes (Blank et al., 1974).

456 S.S. SCHERER

Fig. 2. Schematic drawing of the paranodal region, depicting the glial-axonal specializations seen by freeze-fracture electron microscopy. The fracture plane inside the glial membrane has been illus- trated as a plane that can be viewed from either side to disclose the glial P face and E face. “The interglial junctions consist of junctions between consecutive gyres in the helix of glial loops (GL). One or two lines of tight junctions (TJ) follow the margin on the interglial P face (GL-GL PF). These ridges may consist of tightly arranged rows of particles or a series of bare of varying length. Occasional gap junctions (GJ) appear between the lines of tight junctions.” (Both the original figure and the quotation are from Sandri et al., 1982, re- printed with permission of Elsevier Science Publishers.)

Cytoskeletal proteins are also present in the incisures and paranodes. Both tight and adherens junctions are associated with a variety of cytoskeletal proteins (Anderson et al., 1993; Koch and Franke, 1994; Nagafuchi et al., 1993), including spectrin and actin. In other epithelia, the adhesive properties of E-cadherin depend on other associated cytoskeletal proteins such as the catenins (Buxton and Magee, 1992; Garrod, 1993; Nagafuchi et al., 1993). Thus, one anticipates that many of these cytoskeletal proteins will also be found in the paranodes and incisures, which to date have been shown to contain actin, spectrin, and catenins (Fannon et al., 1995; Kordeli et al., 1990; Trapp et al., 1989b).

Alkaline Phosphatase The demonstration of alkaline phosphatase activity

in the incisures and paranodes of myelinating Schwann cells was the first indication that these structures have a similar and unique molecular composition (Pinner and Campbell, 1965; Pinner et al., 1964).

Ion Channels Schwann cells have been found to express a wide

variety of ion channels (Bevan, 1990; Chiu, 1991; Ritchie, 1992). Voltage-dependent sodium channels appear to be expressed uniformly in the Schwann cell membrane (Elmer et al., 1990). Potassium channels have been found in myelinating Schwann cells, and at least one is enriched in the paranodal region (Wilson and Chiu, 1990). Several members of the Shaker-like family of potassium channels have been found in Schwann cells: Kvl.1, Kv1.2, and Kv1.5 (Chiu et al., 1994; Mi et al., 1994). In the brain, Kvl.1- and Kv1.2- immunoreactivity co-localized in the paranodal region of the axolemma but was not seen in the glial cells (Wang et al., 1993), whereas in peripheral nerve, Kvl.1-immunoreactivity was also found in the cytoplasm of myelinating Schwann cells, but not at paranodes (Mi et al., 1994). Kvl.5-immunoreactivity was found on the external surface of Schwann cell membranes as they curve in towards the node, but not in the axolemma (Mi et al., 1994). Thus, Kv1.5 is the only potassium channel found to date that is enriched in the paranodal region of myelinating Schwann cells, although Kv1.2 has not yet been localized.

Gangliosides Two gangliosides, GDlb and GQlb, have been found

in the paranodes (Chiba et al., 1993; Kusunoki et al., 1993). As discussed above, GDlb has a Gal(pl-3)Gal- NAc epitope, which is recognized by PNA and many so-called anti-GM1 antibodies (Apostolski et al., 19941, so that GDlb could be involved in the pathogenesis of neuropathies that are associated with high titers of anti-GM1 antibodies. Antibodies against GQlb may be involved in the pathogenesis of the Miller Fisher vari- ant of Guillain-Barre syndrome (GBS), which is an acute, demyelinating neuropathy that selectively affects certain cranial nerves (Ropper et al., 1991). Chiba et al. (1993) found modestly higher amounts of GQlb in one commonly affected cranial nerve (the oculomotor) than in the dorsal or ventral roots. They also demon- strated that patients with Miller Fisher syndrome had significantly higher titers of anti-GQlb antibodies than patients with typical GBS, and that the anti- GQlb titer fell promptly after the onset of disease. These data strongly support a role for autoantibodies against GQlb in the pathogenesis of Miller Fisher syndrome.

As discussed above, the presence of antibodies against GM1, GDlb, and GQlb has received much at- tention as a possible cause of various acquired inflam- matory peripheral neuropathies (Chiba et al., 1993; Kinsella et al., 1994; Kornberg et al., 1994; Kusunoki et al., 1994; Sadiq et al., 1990; Vriesendorp et al., 1994; Yuki et al., 1993). Yet, only GDlb and GQlb have been localized in nerve, and their localization in the paranodal region is consistent with the idea that antibodies against them might cause demyelination. Peripheral nerve contains a large number of gangliosides besides GM1, GDlb, and GQlb, including several that appear to be in the myelin fraction. According to Ogawa-Gota et al. (1992), the most abundant gangliosides in human


Fig. 3. Immunohistochemical localization of MAG in peripheral nerve. These are transverse (A and B) and longitudinal sections of adult rat sciatic nerve, labeled with an antiserum against MAG. A and C are 1 pm thick epoxy sections developed with peroxidase-anti- peroxidase method; the density of staining represents the amount of MAG. (B and D) are ultrathin cryosections stained by the immunogold technique; the number of gold particles represents the amount of MAG. Adaxonal MAG-immunoreactivity is found around every my-

Fig. 4. Immunohistochemical localization of E-cadherin in peripheral nerve. This is a longitudinal ultrathin cryosection of rat sciatic nerve, stained with an antibody against E-cadherin, and visualized by immunogold. The gold particles are associated with an adherens junction at a paranode. Scale bar: 0.1 pm. This figure was kindly provided by Drs. Allison Fannon, Diane Sherman, and David Colman (Fannon et al., 1995).

nerve roots (from most to least abundant) are LM1 (sia- losylneolactotetraosylceramide), GD3, and GM1; GM3, GDla, GDlb, X1 (sialosyl-nLc,Cer), and X2 (disialosyl-

elinated axon (some of which are labeled Ax); this is circular in transverse sections (A), and linear in longitudinal sections (0. The adaxonal MAG-immunoreadivity is relatively lighter than that in incisures (B, and large armwheads in A and C) and paranodal regions (D, and small arrowheads in C). Scale bars: 0.2 pm (B,D); the scale bar in panel D equals 20 pm in A and B. These photomicrographs and figure legend are based on the work of Trapp et al. (1989a,b), and were kindly provided by Dr. Bruce Trapp.

nLc,Cer) are present in lower amounts (l-lO%). These workers did not note the presence of GQlb in their material, but Chiba et al. (1993) found GQlb in similar material. At this time, only GDlb, GQlb, and, albeit indirectly, GM1 have been localized to the myelin sheath. The localization of these other gangliosides within the myelin sheath, and determining whether any of them are the targets of autoantibodies in patients with neuropathy, remains to be accomplished.

AXON The dense undercoating of the nodal axolemma in

transmission electron microscopy and the arrangement of intramembranous particles in freeze-fracture have long been taken as evidence of molecular specialization of the nodal and paranodal axolemma (Peters et al., 1991; Quick and Waxman, 1977; Sandri et al., 1982). The molecules that are known to contribute to the nodal axolemmal specialization include voltage-dependent sodium channels, spectrin, ankyrin, and Na + /K + - ATPase. Ritchie and Rogart (1977) deduced that sodium channels probably were highly concentrated in nodal axolemma by showing that the amount of 3H- saxitonin binding was roughly the same in intact and homogenized nerve. After the appropriate antibodies were developed, sodium channels were shown to be localized to the nodal axolemma of the CNS and PNS by

Fig. 5. Irnmunohistochemical localization of Cx32 in peripheral nerve. These are teased fibers of adult rat sciatic, double-labeled with a monoclonal antibody against Cx32 (A,B) and a rabbit polyclonal antibody against rat Po (C). Cx32 is predominately found at the incisures (arrowheads) and paranodes (arrows), whereas the Po is found in the compact myelin sheath. Scale bars: 10 pm.


immunohistochemistry (Black et al., 1989; Elmer et al., 1990). The cytoskeletal proteins spectrin and the “restrictedlerythrocyte” isoform of ankyrin have also been localized to the internodal axolemma (Koenig and Repasky, 1985; Kordeli et al., 1990). The co-localization of these proteins is probably more than a coinci- dence, as both spectrin and restricted ankyrin physi- cally associate with the nodal sodium channels (Srinivasan et al., 1988). The clustering of sodium channels in vitro depends on axon-Schwann cell contact, and occurs in the absence of any restriction in the localization of axonal spectrin or ankyrin (Joe and An- gelides, 1992). The enzyme Na+/K+-ATPase was first localized to the nodal axolemma of CNS axons in goldfish, and subsequently to the nodal axolemma in peripheral nerve (Ariyasu et al., 1985; Schwartz et al., 1981; Wood et al., 1977)

ACKNOWLEDGMENTS This work was supported by the NIH (NS 01565 and

NS 080751, and a grant from the McCabe Fund to S.S.S.. I thank Drs. Allison Fannon, Diane Sherman, and David Colman for providing the electron micro- graph of E-cadherin localization, and Dr. Bruce Trapp for providing the light and electron micrographs of myelin-associated glycoprotein localization. Drs. David Paul and David Colman generously provided the monoclonal antibody against connexin32 and the polyclonal antiserum against Po, respectively.

REFERENCES Abood, L.G., and Abul-Haj, S.K. (1956) Histochemistry and charac-

terization of hyaluronic acid in axons of peripheral nerve. J. Neu- rochem., 1:119-125.

Anderson, J.M., Balda, M.S., and Fanning, A.S. (1993) The structure and regulation of tight junctions. CUR. Opin. Cell Biol., 5772-778.

Apostolski, S., Sadiq, S.A., Hays, A,, Corbo, M., Suturkova, L., Cha- liff, p., Stefansson, K., LeBaron, R.G., Ruoslahti, E., Hays, A.P., and Latov, N. (1994) Identification of Gal(p1-3)GalNAc bearing glycoproteins at the nodes of Ranvier in peripheral nerve. J. Neurosci.

Ariyasu, R.G., Nichol, J.A., and Ellisman, M.H. (1985) Localization of sodium/potassium adenosine triphosphatase in multiple cell types of the murine nervous system with antibodies raised against the enzyme from kidney. J. Neurosci., 52581-2596.

Bennett, M.V.L., Barrio, L.C., Bargiello, T.A., Spray, D.C., Hertsberg, E., and Saez, J.C. (1991) Gap junctions: New tools, new answers, new questions. Neuron, 6:305-320.

Bergoffen, J., Scherer, S.S., Wang, S., Oronzi-Scott, M., Bone, L., Paul, D.L., Chen, K., Lensch, M.W., Chance, P., and Fischbeck, K. (1993) Connexin mutations in X-linked Charcot-Marie-Tooth disease. Sci- ence, 262:2039-2042.

Bevan, S. (1990) Ion channels and neurotransmitter receptors in glia. Semin. Neurosci., 2:467-481.

Black, J.A., Fiedman, B., Waxman, S.G., Elmer, L.N., and Angelides, K.J. (1989) Immunoultrastructural localization of sodium channels at nodes of lamina and astrocytes in rat optic nerve. Proc. R. Soc.

Res., 38134-141.

Lond. B, 238:39-51. Blanchard, C.E., Mackenzie, M.L., Sikri, K., and Allt, G. (1985) Fil-

ipin-sterol complexes at nodes of Ranvier. J . Neurocytol., 14:1053- 1062.

Blank,W.F., Jr., Bunge, M.B., and Bunge, R.P. (1974) The sensitivity of the myelin sheath, particularly the Schwann cell-axolemmal junction, to lowered calcium levels in cultured sensory ganglia. Brain Res., 67:503-518.

Boller, K., Vestweber, D., and Kemler, R. (1985) Cell-adhesion molecule uvomorulin is localized in the intermediate junctions of adult intestinal epithelial cells. J. Cell Biol., 100:327-332.

Braun, P.E., Frail, D.E., and Latov, N. (1982) Myelin-associated gly-

coprotein is the antigen for a monoclonal IgM in polyneuropathy. J. Neurochem., 391261-1265.

Brennan, M.J., David, J.L., Kenimer, J.G., and Manclark, C.R. (1988) Lectin-like binding of pertussis toxin to a 165-kilodalton Chinese hamster ovary cell glycoprotein. J. Biol. Chem., 263:4895-4899.

Buxton, R.S., and Magee, A.I. (1992) Structure and interactions of desmosomal and other cadherins. Semin. Cell Biol., 3:157-167.

Carey, D.J., Evans, D.M., Stahl, R.C., Asundi, V.K., Conner, K.J., Garbes, P., and Cizmeci-Smith, G. (1992) Molecular cloning and characterization of N-syndecan, a novel transmembrane heparan sulfate proteoglycan. J. Cell Biol., 117:191-201.

Carey, D.J., Stahl, R.C., Asundi, V.K., and Tucker, B. (1993) Process- ing and subcellular distribution of the Schwann cell lipid-anchored heparan sulfate proteoglycan and identification as glypican. Exp. Cell Res.. 20810-18.

Chance, P.F.,andPleasure, D. (1993) Charcot-Marie-Tooth syndrome. Arch. Neurol., 501180-1183.

Chaudhry, V., Corse, A.M., Cornblath, D.R., Kuncl, R.W., Drachman, D.B., Freimer, M.L., Miller, R.G., and Griffin, J.W. (1993) Multifo- cal motor neuropathy: Response to human immune globulin. Ann. Neurol., 33:237-242.

Chiba, A., Kusunoki, S., Obata, H., Machinami, R., and Kanazawa, I. (1993) Serum anti-GQ,, IgG antibody is associated with ophthal- moplegia in Miller Fisher syndrome and Guillain-Barre syndrome: Clinical and immunohistochemical studies. Neurology, 43:1911- 1917.

Chiu, A.Y., and KO, J. (1994) A novel epitope of entactin is present at the mammalian neuromuscular junction. J . Neurosci., 14:2809- 2817.

Chiu, S.Y. (1991) Functions and distribution of voltage-gated sodium and potassium channels in mammalian Schwann cells. Glia, 4:541- 558.

Chiu, S.Y., Scherer, S.S., Blonski, M., Kang, S.S., and Messing, A. (1994) Axons regulate the expression of Shaker potassium channel genes in Schwann cells in peripheral nerve. Glia, 12:l-11.

Chou, K.H., Nolan, C.E., and Jungalwala, F.B. (1985) Subcellular fractionation of rat sciatic nerve and specific localization of ganglioside LM, in rat nerve myelin. J . Neurochem., 44:1898-1912.

Corbo, M., Quattrini, A., Latov, N., and Hays, A.P. (1993) Localization of GM1 and Gal(p1-3)GalNAc antigenic determinants in peripheral nerve. Neurology, 432309-814.

Daniloff, J.K., Crossin, K.L., Ancon-Raymond, M., Murawsky, M., Reiger, F., and Edelman, G.M. (1989) Expression of cytotactin in the normal and regenerating neuromuscular system. J . Cell Biol., 108:623-635.

Deluech. A.. Firard. N.. and Delmch, B. (1982) Localization of hyaluronectin in the nervous system. Brain Res., 245:251-257.

Dermietzel, R., Hwang, T.K., and Spray, D.S. (1990) The gap junction family: Structure, function and chemistry. Anat. Embryol., 182: 517-528.

Devor, M., Govrin-Lippmann, R., and Angelides, K. (1993) Na’ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J. Neuro- sci., i3:1976-1992.

Ehrie. K.. Leivo. I.. Armaves, W.S., Ruoslahti, E., and Enpal l , E. (1%) Merosin, tissu~-specific basement membrane protein, is a laminin-like protein. Proc. Natl. Acad. Sci. U.S.A., 87:3264-3268.

Eldridge, C.F., Sanes, J.R., Chiu, A.Y., Bunge, R.P., and Cornbrooks, C.J. (1986) Basal lamina-associated heparan sulfate proteoglycan in the rat PNS: Characterization and localization using monoclonal antibodies. J. Neurocytol., 1537-51.

Elmer, L.W., Black, J.A., Waxman, S.G., and Angelides, K.J. (1990) The voltage-dependent sodium channel in mammalian CNS and PNS: antibody characterization and immunocytochemical localization. Brain Res., 532:222-231.

Fairweather, N., Bell, C., Cochrane, S., Chelly, J., Wang, S., Mostac- ciuolo, M.L., Monaco, A.P., and Haites, N.E. (1994) Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Twth disease (CMT-Xl). Hum. Mol. Genet., 3:29-34.

Fannon, A.M., Sherman, D.L., Ilyina-Gragerova, G., Brophy, P.J., Friedrich, V.L., and Colman, D.R. (1995) Novel E-cadherin mediated adhesion in peripheral nerve: Schwann cell architecture is stabilized by autotypic adherens junctions. J. Cell Biol. 129: 189- 202.

Farquhar, M.G., and Palade, G.E. (1963) Junctional complexes in various epithelia. J. Cell Biol., 17:375-412.

Fishman, P.H. (1982) Role of membrane gangliosides in the binding and action of bacterial toxins. J. Membr. Biol., 6985-97.

460 S.S. SCHERER

Freddo, L., Yu, R.K., Latov, N., Donofrio, P.D., Hays, A.P., Greenberg, H.S., Albers, J.W., Allessi, A.G., and Keren, D. (1986) Gangliosides GM, and GD,, are antigens for IgM M-protein in a patient with motor neuron disease. Neurology, 36454-458.

Friend, D.S., and Gilula, N.B. (1972) Variations in tight junctions and gap junctions in mammalian tissues. J. Cell Biol., 53:758-776.

Ganser, A.L., Kirschner, D.A., and Willinger, M. (1983) Ganglioside localization on myelinated nerve fibres by cholera toxin binding. J. Neurocytol., 12921-938.

Garrod, D.R. (1993) Desmosomes and hemidesmosomes. Curr. Opin. Cell Biol., 5:30-40.

Giese, K.P., Martini, R., Lemke, G., Soriano, P., and Schachner, M. (1992) Mouse Po gene disruption leads to hypomyelination, abnor- mal expression i c recognition molecules, and degeneration of myelin and axons. Cell, 71:565-576.

Haefliger, J.-A., Bruzzone, R., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., and Paul, D.L. (1992) Four novel members of the connexin family of gap junction proteins. J. Biol. Chem., 267:2057-2064.

Hammer, J.A., O'Shannessy, D.J., De Leon, M., Gould, R., Zand, D., Daune, G. and Quarles, R.H. (1993) Immunoreactivity of PMP-22, PO, and other 19 to 28 kDa glycoproteins in peripheral nerve myelin of mammals and fish with HNKl and related antibodies. J. Neurosci. Res., 35546-558.

Hess, A., and Young, J.Z. (1952) The nodes of Ranvier. Proc. R. Soc. Lond. B, 140301-320.

Joe, E.H., and Angelides, K. (1992) Clustering of voltage-dependent sodium channels on axons depends on Schwann cell contact. Na- ture, 356:333-335.

Kinsella, L.J., Lange, D.L., Trojaborg, W., Sadiq, S.A., Younger, D. S., and Latov. N. (1994) Clinical and e1ectmDhysioloEid correlates of elevated anti-GM, antibody titers. Neuroligy, 44y1278-1282.

Koch, P.J., and Franke, W.W. (1994) Desmosomal cadherins: Another growing multigene family of adhesion molecules. Curr. Opin. Cell Biol., 6i682-687.

Koenig, E., and Repasky, E. (1985) A regional analysis of a-spectrin in the isolated Mauthner neuron and in isolated axon8 of the goldfish and rabbit. J. Neurosci., 5705-714.

Kordeli, E., Davis, J., Trapp, B., and Bennett, V. (1990) An isoform of ankyrin is localized at nodes of Ranvier in myelinated axons of central and peripheral nerves. J. Cell Biol., 1101341-1352.

Kornberg, A.J., Pestronk, A,, Bieser, K., Lo, T.W., McKhann, G.M., Wu, H.S., and Jiang, Z. (1994) The clinical correlates of high-titer IgG anti-GM1 antibodies. Ann. Neurol., 35234-237.

Kusunoki, S., Chiba, A., Tai, T., and Kanazawa, I. (1993) Localization of GM1 and GDlb antigens in the human peripheral nervous system. Muscle Nerve, 16:752-756.

Kusunoki, S., Chiba, A,, Kon, K., Ando, S., Arisawa, K., Tate, A,, and Kanazawa, I. (1994) N-acetylgalactosaminyl GDla is a target molecule for serum antibody in Guillain-Barre syndrome. Ann. Neu- rol., 35570-576.

Landon, D.N., and Langley, O.K. (1971) The local chemical environ- ment of nodes of Ranvier: A study of cation binding. J. Anat., 108: 419-432.

Latov, N. (1990) Antibodies to glycoconjugates in neurologic disease. Clinical Aspects Autoimmunity, 418-29.

Lemke, G. (1992) Myelin and myelination. In: Molecular Neurobiol- ogy, Z.W. Hall, ed. Sunderland, MA, Sinauer, pp. 281-312.

Lemke, G., and Axel, R. (1985) Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell, 40501-508.

Li, C., Topak, M.B., Gerial, R., Calpoff, S., Abramow-Newerly, W., Trapp, B., Peterson, A,, and Roder, J . (1994) Myelination in the absence of myelin-associated glycoprotein. Nature, 369:747-750.

Lorirnier, P., Mezin, P., Moleur, F.L., Pinel, N., Peyrol, S., and Stoeb- ner, P. (1992) Ultrastructural localization of the major components of the extracellular matrix in normal rat nerve. J. Histochem. Cy- tochem., 40859-868.

Lupski, J.R., Montes de Oca-Luna, R., Slaugenhaupt, S., Pentao, L., Guzzetta, V., Trask, B.J., Saucedo-Cardenas, O., Barker, D.F., Chakravarti, A., and Patel, P.I. (1991) DNA duplication associated with Charcot-Marie-Tooth disease type IA. Cell, 66:219-232.

Martini, R. (1994) Expression and functional roles of neural cell surface molecules and extracellular matrix components during development and regeneration of peripheral nerves. J . Neurocytol., 23: 1-28.

Martini, R., Schachner, M., and Faissner, A. (1990) Enhanced expression of the extracellular matrix molecule JUtenascin in the regenerating adult mouse sciatic nerve. J . Neurocytol., 19:601-616.

McKhann, G.M., Cornblath, D.R., Griffin, J.W., Ho, T.W., Li, C.Y., Jiang, Z., Wu, H.S., Zhaori, G., Liu, Y., Jou, L.P., Liu, T.C., Gao, C.Y., Mao, J.Y., Blaser, M.J., Mishu, B., and Asbury, A.K. (1993) Acute motor axonal newpathy: A frequent cause of acute flaccid paralysis in China. Ann. Neurol., 33:333-342.

Mege, R.M., Nicolet, M., Pincon-Raymond, M., Murawsky, M., and Rieger, F. (1992) Cytotactin is involved in synaptogenesis during regeneration of the frog neuromuscular system. Dev. Biol., 149:

Mi, H., Deerinck, T., Ellisman, M.H., and Schwartz, T.L. (1994) Dif- ferential distribution of closely related Shaker-like K+ channels in rat Schwann cells. SOC. Neurosci. Abstr., 20:76.

Mikol, D.D., and Stefansson, K. (1988) A phosphatidylinositol-linked peanut agglutinin-binding glycopmtein in central nervous system myelin and on oligodendrocytes. J. Cell Biol., 106:1273-1279.

Mikol, D.D., Gulcher, J.R., and Stefansson, K. (1990) The oligodendrocyte myelin glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate. J. Cell Biol., 110:471-479.

Mirky, R., and Jessen, K.R. (1990) Schwann cell development and the regulation of myelination. Semin. Neurosci., 2:423-435.

Momoi, T., Tokunaga, T., and Nagai, Y. (1982) Specific interaction of peanut agglutinin with the glycolipid asialo GM1. FEBS Lett., 141: 6-10.

Montag, D., Giese, K.P., Bartsch, U., Martini, R., Lang, Y., Bluth- mann, H., Karthigasan, J., Kirschner, D.A., Wintergerst, E.S., Nave, K.-A,, Zielasek, J., Toyka, K.V., Lipp, H.-P., and Schachner, M. (1994) Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron, 13:229-246.

Nagafuchi, A., Tsukita, S., and Takeichi, M. (1993) Transmembrane control of cadherin-mediated cell-cell adhesion. Semin. Cell Biol.,

Ogawa-Goto, K., Funamoto, N., Ohta, Y., Abe, T., and Nagashima, K. (1992) Myelin gangliosides of human peripheral nervous system: An enrichment of GM1 in the motor nerve myelin isolated from cauda equina. J. Neumhem., 591844-1849.

Peters, A., Palay, S.L., and Webster, H.d. (1991) The Fine Structure of the Nervous System. New York, Oxford University Press, 494 pp.

Pinner, B., and Campbell, J.B. (1965) Alkaline phosphatase activity of incisures and nodes during degeneration and regeneration of peripheral nerve fibers. Exp. Neurol., 12159-172.

Pinner, B., Davison, J.F., and Campbell, J.B. (1964) Alkaline phosphatase in peripheral nerves. Science, 145:936-938.

Quick, D.C., and Waxman, S.G. (1977) Ferric ion, ferrocyanide, and inorganic phosphate as cytochemical readants at peripheral nodes of Ranvier. J. Neurocytol., 6555-570.

Ranvier, M.A. (1878) Lecons sur Histologie du Systeme Nerveux. Paris, Savy, Rieger, F., Daniloff, J. K., Pincon-Raymond, M., Crossin, K.C., Grumet, M., and Edelman, G. M. (1986) Neuronal cell adhesion molecules and cytotactin are colocalized at the node of Ranvier. J. Cell Biol., 103379-391.

Ritchie, J.M. (1992) Voltage-gated ion channels in Schwann cells and glia. Trends Neurosci., 15:345-351.

Ritchie, J.M., and Rogart, R.P. (1977) Density of sodium channels in mammalian myelinated nerve fibers and nature of the axonal membrane under the myelin sheath. Proc. Natl. Acad. Sci. U.S.A., 7 4

Ritchie, J.M., Black, J.A., Waxman, S.G., and Angelides, K.J. (1990) Sodium channels in the cytoplasm of Schwann cells. Roc. Natl. Acad Sci. U.S.A., 879290-9294.

Ropper, A.H., Wijdicks, E.F.M. and Truax, B.T. (1991) Guillain-Barre Syndrome. Philadelphia, F. A. Davis, 369 pp.

Sadiq, S.A., Thomas, F.P., Kilidireas, K., Protopsaltis, S., Hays, A.P., Lee, K.-W., Romas, S.N., Kumar, N., van den Berg, L., Santoro, M., Lange, D.J., Younger, D.S., Lovelace, R.E., Trojaborg, W., Sherman, W.H., Miller, J.R., Minuk, J., Fehr, M.A., Roelofs, R.I., Hollander, D., Nichols, F.T., 111, Mitsumoto, H., Kelly, J.J., Jr., Swift, T.R., Munsat, T.L., and Latov, N. (1990) The spectrum of neurologic disease associated with anti-GM, antibodies. Neurology, 401067- 1072.

Sandri, C., Van Buren, J.M., and Akert, K. (1982) Membrane mor- phology of the vertebrate nervous system. Prog. Brain Res., 46201- 265.

Sanes, J.R., Engvall, E., Butkowsky, R., and Hunter, D.D. (1990) Mo- lecular heterogeneity of basal laminae: Isoforms of laminin and collagen IV a t neuromuscular junction and elsewhere. J . Cell Biol., 111:1685-1699.

Santoro, M., Thomas, F.P., Fink, M.E., Lange, D.J., Uncini, A., Wadia, N.H., Latov, N., and Hays, A.P. (1990) IgM deposits at nodes of

381-394.

4: 175 -181.

211-215.


Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block. Ann. Neurol., 28:373-377.

Schwartz, M., Ernst, S.A., Siegel, G.J., and Agranoff, B. (1981) Im- munocytochemical localization of (Na', K+)-ATPase in the goldfish optic nerve. J. Neurochem., 36107-115.

Srinivasan, Y ., Elmer, L., Davis, H., Bennett, V., and Angelides, K. (1988) Ankyrin and spectrin associate with voltage-dependent sodium channels in brain. Nature, 333:177-180.

Streit, W.J., Schulte, B.A., Spicer, S.S., and Balentine, J. D. (1985) Histochemical localization of galactose-containing glycoconjugate at peripheral nodes of Ranvier in the rat. J. Histochem. Cytochem., 33:33-39.

Suter, U., Welcher, A.A., and Snipes, G.J. (1993) Progress in the molecular understanding of hereditary peripheral neuropathies re- veals new insights into the biology of the peripheral nervous system. Trends Neurosci., 1650-56.

Takeichi, M. (1990) Cadherins: A molecular family important in se- lective cell-cell adhesion. Annu. Rev. Biochem., 59:237-252.

Thomas, F.K., Trajaborg, W., Nagy, C., Santoro, M., Sadiq, S.A., Latov, N., and Hays, A.P. (1991) Experimental autoimmune neuropathy with anti-GM1 antibodies and immunoglobulin deposits at the nodes of Ranvier. Acta Neuropathol., 82:378-383.

Thomas, P.K., and Ochoa, J. (1984) Microscopic anatomy of peripheral nerve fibers. In: Peripheral Neuropathy, P.J. Dyck, P.K. Thomas, E.H. Lambert, and R. Bunge, eds. Philadelphia, W.B. Saunders, pp.

Tona, A., Perides, G., Rahemtulla, F., and Dahl, D. (1993) Extracel- lular matrix in regenerating rat sciatic nerve: A comparative study on the localization of laminin, hyaluronic acid, and chondroitin sulfate proteoglycans, including versican. J. Histochem. Cytochem.,

Trapp, B.D., and Quarles, R.H. (1984) Immunocytochemical localization of the myelin-associated glycoprotein. Fact or artifact? J. Neu- roimmunol . , 6 2 3 1-249.

39-96.

41593499.

Trapp, B.D., Andrew, S.B., Cootaueo, C., and Quarles, R. (1989a) The myelin-associated glycoprotein is enriched in multivesicular bodies and periaxonal membrane of actively myelinating oligodendrocytes. J. Cell Biol., 109:2417-2425.

Trapp, B.D., Andrews, S.B., Wong, A., O'Connell, M., andGrifin, J.W. (1989b) Co-localization of the myelin-associated glycoprotein and the microfilament components, F-actin and spectrin, in Schwann cells of myelinated nerve fibers. J . Neurocytol., 18:47-60.

Vriesendorp, F.J., Mishu, B., Blaser, MJ., and Koski, C.L. (1994) Serum antibodies to GMl, GDlb, peripheral nerve myelin, and Campylobacter jejuni, in patients with Guillain-Barre syndrome and controls: Correlation and prognosis. Ann. Neurol., 34:130-135.

Wang, H., Kunkel, D.D., Martin, T.M., Schwartkroin, P.A., and Tem- pel, B.L. (1993) Heteromultimeric K' channels in terminal and jwtaparanodal regions of neurons. Nature, 365:75-79.

Waxman, S.G., and Black, J.A. (1987) Macromolecular structure of the Schwann cell membrane. Perinodal microvilli. J. Neurol. Sci., 77:23-34.

Webster, H.d., and Favilla, J.T. (1984) Development of peripheral nerve fibers. In: Peripheral Neuropathy. P.J. Dyck, P.K. Thomas, E.H. Lambert, and R. Bunge, eds. Philadelphia, W.B. Saunders, pp. 329-359.

Willecke, K., Hennemann, H., Dahl, E., Jungbluth, S., and Heynkes, R. (1991) The diversity of connexin genes encoding gap junctional proteins. Eur. J . Cell Biol., 56:l-7.

Wilson, G.F.. and Chiu, S.Y. (1990) Ion channels in axon and Schwann cell membranes at paranodes of mammalian myelinated fibers studied with patch clamp. J. Neurosci., 10:3263-3274.

Wood, J.G., Jean, D.H., Whitaker, J.N., McLaughlin, B.J., and Albers, R.W. (1977) Immunocytochemical localization of the sodium, potassium activated ATPase in knifefish brain. J. Neurocytol., 6571- 581.

Yuki, N., Yamada, M., Sato, S., Ohama, E., Kawase, Y., Ikuta, F., and Miyatake, T. (1993) Association of IgG anti-GDla antibody with severe Guillain-Barre syndrome. Muscle Nerve, 16642-647.

molecular specializations at nodes and paranodes in peripheral nerve

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