Development of axonal membrane specializations defines nodes of Ranvier and precedes Schwann cell myelin elaboration

The development of the node of Ranvier has been previously described using thin-section electron microscopy. Using freeze-fracture, we have examined the development of glial and axonal membrane specializations before and during myelination. The spinal roots of the newborn rat are composed of bundles of unmyelinated and partially myelinated axons. At this early stage of development, the axons are engulfed by Schwann cells, while certain axons are segregated into a one to one relationship with myelinating cells. Patches of uniformly shaped 150- to 300-Å particles are readily distinguished against a relatively nonparticulate axonal E face. Patches of less uniform particles are found in the axonal P face, however, they are difficult to distinguish from a particulate background. Thin processes are found closely applied to the axonal membrane on the sides of a particle patch. While engulfing the axon with one or two noncompacted windings, the Schwann cell is predominantly restricted to one side of such a particle patch. As the number of windings covering the axon increases, so does the size of the particle patch, until an annulus of particles, similar to that of an adult node, is observed. The paucity of isolated particle patches in axolemma suggests that recognition and segregation of axons by Schwann cells are followed by a rapid initiation of myelination. Throughout the early periods of myelination there is evidence of endocytotic and exocytotic events at the nodal membrane associated with the appearance of 230-Å dimeric particles in the axolemma. Despite the paucity of windings and complete absence of compaction, the fracture faces of the glial and axonal membranes show linear organizations of particles. Scalloped regions in the P face of the nodal axolemma display dimeric-particle rows oriented along the scallop. These rows adopt a more circumferential orientation when the overlying glial process is wound into a paranodal location. While the spacing of dimeric-particle rows is maintained at a constant 360 Å, the number of rows per scallop necessarily decreases with compaction of the paranodal loops until a state similar to that of the adult, in which there are approximately two rows per scallop, is reached. In regions of close apposition between axon and Schwann cell, a linear arrangement of 160- and 75-Å particles in the glial fracture faces occurs prior to the appearance of tight junctions between glial loops and prior to compaction. Though the paranodes on each side of most nodes observed developed symmetrically, some asymmetric half-nodes have been observed.     

Freeze-fracture studies on unmyelinated axolemma of rat cervical sympathetic trunk: correlation with saxitoxin binding

The density and diameter distributions of intramembranous particles (IMPs) within unmyelinated axolemma from rat cervical sympathetic trunk were examined with freeze-fracture electron microscopy. The axolemma displays a highly asymmetrical partitioning of IMPs with ca. 1200 IMPs microns-2 on P-faces and ca. 100 IMPs microns-2 on E-faces. Particle sizes (diameters) are unimodally distributed on both fracture faces, with a range from 2.4 nm to 15.6 nm. Approximately 16% of the particles on P-faces and 28% of particles on E-faces are of a large (greater than 9.6 nm) diameter. On both fracture faces, the IMPs appear to be randomly distributed; no aggregations of particles were observed. The results indicate that there are ca. 230 large IMPs microns-2 of unmyelinated axolemma from rat cervical sympathetic trunk. The density of these IMPs is similar to the density of saxitoxin binding sites on unmyelinated axolemma from rat cervical sympathetic trunk (Pellegrino et al. 1984 (Brain Res. 305, 357-360)), which suggests that many of the large diameter particles may be the morphological correlate of voltage-sensitive Na+ channels.     

Neurofascin is a glial receptor for the paranodin/Caspr-contactin axonal complex at the axoglial junction

In myelinated fibers of the vertebrate nervous system, glial-ensheathing cells interact with axons at specialized adhesive junctions, the paranodal septate-like junctions. The axonal proteins paranodin/Caspr and contactin form a cis complex in the axolemma at the axoglial adhesion zone, and both are required to stabilize the junction. There has been intense speculation that an oligodendroglial isoform of the cell adhesion molecule neurofascin, NF155, expressed at the paranodal loop might be the glial receptor for the paranodin/Caspr-contactin complex, particularly since paranodin/Caspr and NF155 colocalize to ectopic sites in the CNS of the dysmyelinated mouse Shiverer mutant. We report that the extracellular domain of NF155 binds specifically to transfected cells expressing the paranodin/Caspr-contactin complex at the cell surface. This region of NF155 also binds the paranodin/Caspr-contactin complex from brain lysates in vitro. In support of the functional significance of this interaction, NF155 antibodies and the extracellular domain of NF155 inhibit myelination in myelinating cocultures, presumably by blocking the adhesive relationship between the axon and glial cell. These results demonstrate that the paranodin/Caspr-contactin complex interacts biochemically with NF155 and that this interaction is likely to be biologically relevant at the axoglial junction.     

Disrupted axo-glial junctions result in accumulation of abnormal mitochondria at nodes of ranvier

Mitochondria and other membranous organelles are frequently enriched in the nodes and paranodes of peripheral myelinated axons, particularly those of large caliber. The physiologic role(s) of this organelle enrichment and the rheologic factors that regulate it are not well understood. Previous studies suggest that axonal transport of organelles across the nodal/paranodal region is locally regulated. In this study, we have examined the ultrastructure of myelinated axons in the sciatic nerves of mice deficient in the contactin-associated protein (Caspr), an integral junctional component. These mice, which lack the normal septate-like junctions that promote attachment of the glial (paranodal) loops to the axon, contain aberrant mitochondria in their nodal/paranodal regions. These mitochondria are typically large and swollen and occupy prominent varicosities of the nodal axolemma. In contrast, mitochondria located outside the nodal/paranodal regions of the myelinated axons appear normal. These findings suggest that paranodal junctions regulate mitochondrial transport and function in the axoplasm of the nodal/paranodal region of myelinated axons of peripheral nerves. They further implicate the paranodal junctions in playing a role, either directly or indirectly, in the local regulation of energy metabolism in the nodal region.     

Molecular structure of the axolemma of developing axons following altered gliogenesis in rat optic nerve

Axonal and axolemmal development of fibers from rat optic nerves in which gliogenesis was severely delayed by systemic injection of 5-azacytidine (5-AZ) was examined by freeze-fracture electron microscopy. In neonatal (0-2 days) rat optic nerves, all fibers lack myelin, whereas in the adult, virtually all axons are myelinated. The axolemma of neonatal premyelinated fibers is relatively undifferentiated. The P-fracture face (P-face) displays a moderate (approximately 550/micron 2) density of intramembranous particles (IMPs), whereas the E-fracture face (E-face) has few IMPs (approximately 125/micron 2) present. By 14 days of age, approximately 25% of the axons within control optic nerves are ensheathed or myelinated, with the remaining axons premyelinated. The ensheathed and myelinated fibers display increased axonal diameter compared to premyelinated axons, and these larger caliber fibers exhibit marked axonal membrane differentiation. Notably, the P-face IMP density of ensheathed and myelinated fibers is substantially increased compared to premyelinated axolemma, and, at nodes of Ranvier, the density of E-face particles is moderately high (approximately 1300/micron 2), in comparison to internodal or premyelinated E-face axolemma. In optic nerves from 14-day-old 5-AZ-treated rats, few oligodendrocytes are present, and the percentage of myelinated fibers is markedly reduced. Despite delayed gliogenesis, some unensheathed axons within 5-AZ-treated optic nerves display an increased axonal diameter compared to premyelinated fibers. Most of these large caliber fibers also exhibit a substantial increase in P-face IMP density. Small (less than 0.4 micron) diameter unensheathed axons within treated optic nerves maintain a P-face IMP density similar to that of control premyelinated fibers. Regions of increased E-face particle density were not observed. The results demonstrate that some aspects of axolemma differentiation continue despite delayed gliogenesis and the absence of glial ensheathment, and suggest that axolemmal ultrastructure is, at least in part, independent of glial cell association.     

An isoform of ankyrin is localized at nodes of Ranvier in myelinated axons of central and peripheral nerves

Two variants of ankyrin have been distinguished in rat brain tissue using antibodies: a broadly distributed isoform (ankyrinB) that represents the major form of ankyrin in brain and another isoform with a restricted distribution (ankyrinR) that shares epitopes with erythrocyte ankyrin. The ankyrinR isoform was localized by immunofluorescence in cryosections of rat spinal cord gray matter and myelinated central and peripheral nerves to: (a) perikarya and initial axonal segments of neuron cells, (b) nodes of Ranvier of myelinated nerve with no detectable labeling in other areas of the myelinated axons, and (c) the axolemma of unmyelinated axons. Immunogold EM on ultrathin cryosections of myelinated nerve showed that ankyrinR was localized on the cytoplasmic face of the axolemma and was restricted to the nodal and, in some cases, paranodal area. The major isoform of ankyrin in brain (ankyrinB) displayed a broad distribution on glial and neuronal cells of the gray matter and a mainly glial distribution in central myelinated axons with no significant labeling on the axolemma. These results show that (a) ankyrin isoforms display a differential distribution on glial and neuronal cells of the nervous tissue; (b) an isoform of ankyrin codistributes with the voltage-dependent sodium channel in both myelinated and unmyelinated nerve fibers. Ankyrin interacts in vitro with the voltage-dependent sodium channel (Srinivasan, Y., L. Elmer, J. Davis, V. Bennett, and K. Angelides. 1988. Nature (Lond.). 333:177-180). A specific interaction of an isoform of ankyrin with the sodium channel thus may play an important role in the morphogenesis and/or maintenance of the node of Ranvier.     

A molecular view on paranodal junctions of myelinated fibers.

The axoglial paranodal junctions, flanking the Ranvier nodes, are specialized adhesion sites between the axolemma and myelinating glial cells. Unraveling the molecular composition of paranodal junctions is crucial for understanding the mechanisms involved in the regulation of myelination, and positioning and segregation of the voltage-gated Na+ and K+ channels, essential for the generation and conduction of action potentials. Paranodin/Caspr was the first neuronal transmembrane glycoprotein identified at the paranodal junctions. Paranodin/Caspr is associated on the axonal membrane with contactin/F3, a glycosylphosphatidylinositol-anchored protein, essential for its correct targeting. The extra and intracellular regions of paranodin encompass multiple domains which can be involved in protein-protein interactions with other axonal proteins and glial proteins. Thus, paranodin plays a central role in the assembly of multiprotein complexes necessary for the formation and maintenance of paranodal junctions.     

The cytoskeletal adapter protein 4.1G organizes the internodes in peripheral myelinated nerves

Myelinating Schwann cells regulate the localization of ion channels on the surface of the axons they ensheath. This function depends on adhesion complexes that are positioned at specific membrane domains along the myelin unit. Here we show that the precise localization of internodal proteins depends on the expression of the cytoskeletal adapter protein 4.1G in Schwann cells. Deletion of 4.1G in mice resulted in aberrant distribution of both glial adhesion molecules and axonal proteins that were present along the internodes. In wild-type nerves, juxtaparanodal proteins (i.e., Kv1 channels, Caspr2, and TAG-1) were concentrated throughout the internodes in a double strand that flanked paranodal junction components (i.e., Caspr, contactin, and NF155), and apposes the inner mesaxon of the myelin sheath. In contrast, in 4.1G(-/-) mice, these proteins "piled up" at the juxtaparanodal region or aggregated along the internodes. These findings suggest that protein 4.1G contributes to the organization of the internodal axolemma by targeting and/or maintaining glial transmembrane proteins along the axoglial interface.     

Structure of the intramural nerves of the rat bladder

The bladder of adult female rats receives ～16,000 axons (i.e., is the target of that many ganglion neurons) of which at least half are sensory. In nerves containing between 40 and 1200 axons cross-sectional area is proportional to number of axons; >99% of axons are unmyelinated. A capsule forms a seal around nerves and ends abruptly where nerves, after branching, contain ～10 axons. A single blood vessel is present in many of the large nerves but never in nerves of <600 axons. The number of glial cells was estimated through the number of their nuclei. There is a glial nucleus profile every 76 axonal profiles. Each glial cell is associated with many axons and collectively covers ～1,000 μm of axonal length. In all nerves a few axonal profiles contain large clusters of vesicles independent of microtubules. The axons do not branch; they alter their relative position along the nerve; they vary in size along their length; none has a circular profile. All the axons are fully wrapped by glial cells and never contact each other. The volume of axons is larger than that of glial cells (55%–45%), while the surface of glial cell is twice as extensive as that of axons; there are ～2.27 m² of axolemma and ～4.60 m² of glial cell membrane per gram of nerve. Of the mitochondria of a nerve ～3/4 are in axons and ～1/4 in glial cells.     

Glial cells in peripheral nerves of the cockroach, Periplaneta americana

The ultrastructural organization and the junctional complexes of peripheral nerves have been investigated in the cockroach Periplaneta americana. Nerve 5 is surrounded by a layer of connective tissue, the neural lamella, beneath which is a layer of perineurial glial cells wrapping the axons. Adjacent perineurial cells are joined to one another by septate, gap and tight junctions. Septate and gap junctions were observed in freeze-fracture replicas of main trunk nerve 5. Septate junctions were found as rows of PF particles mainly in perineurial cell membranes. Gap junctions exhibited EF macular aggregates in perineurial and subperineurial glial cells. During incubations in vivo with extracellularly applied ionic lanthanum, the lanthanum did not penetrate beyond the perineurium. Where nerve 5 branches and contacts the muscle, lanthanum penetrated freely between the muscle fibres and the nerve branches. In small peripheral branches where the axons are surrounded by single a glial layer, lanthanum is unable to penetrate to the axolemma.     

Developmental changes at the node and paranode in human sural nerves: morphometric and fine-structural evaluation

Developmental alterations of paranodal fiber segments have not been investigated systematically in human nerve fibers at the light- and electron-microscopic level. We have therefore analyzed developmental changes in the fine structure of the paranode in 43 human sural nerves during the axonal growth period up to 5 years of age, and during the subsequent myelin development up to 20 years and thereafter. The nodal, internodal, and paranodal axon diameters reach their adult values at 4–5 years of age. The ratio between internodal and paranodal axon diameters remains constant at 1.8–2.0. Despite a considerable increase in myelin sheath thickness, the length of the paranodal myelin sheath attachment zone at the axon does not increase correspondingly, because of attenuation, separation from the axolemma, and piling up of myelin loops in the paranode. Separation of variable numbers of terminal myelin loops from the underlying axolemma results in the formation of bracelets of Nageotte, whereas the transverse bands of these loops disappear. The adaptation of the paranodal myelin sheath to axonal expansion during development probably occurs by uneven gliding of the paranodal myelin loops simultaneously with internodal slippage of myelin lamellae. Since mechanically stabilizing structures (tight junctions and desmosomes between adjacent paranodal myelin processes; transverse bands between myelin loops and paranodal axolemma) are unevenly arranged, especially during rapid axonal growth, paranodal axonal growth with simultaneous adaptation of the myelin sheath is probably discontinuous with time.Presented in part at the 10th Biennial Meeting of the Peripheral Nerve Study Group at Arden House, Harriman, New York, USA, June 30th–July 3rd, 1991, and as a doctoral thesis (M. Bertram) at the RWTH Aachen in 1991     

Occluding-like junctions at mesaxons of central myelin in Anolis carolinensis are not 'tight'. A freeze-fracture-protein tracer analysis.

The junctional complexes of the myelin sheath of central nervous system axons in the American chameleon, Anolis carolinensis, exhibit an intramembrane ridge and groove construction in freeze-fracture replicas that has usually been interpreted in other organisms as evidence for an occluding or tight intercellular junction. Close examination of PF fracture face ridges, however, shows them to be made up of discontinuous rows of particles of variable length separated by frequent gaps of non-uniform width. Introduction of horseradish peroxidase into the intercellular milieu of the lizard central nervous system is followed by appearance of this protein in interlamellar spaces of the myelin sheath and in the intercellular spaces containing focal membrane fusions that correspond precisely in position and center-to-center spacing to the ridges and grooves in platinum replicas of the same tissue. Since the junctional ridges on PF fracture faces in these mesaxonal junctional complexes are conspicuously discontinuous and since the areas within the myelin sheath where these junctional complexes are located inner and outer mesaxons) are readily permeated by exogenous protein tracer, it is concluded that the junctional complexes of central myelin mesaxons, heretofore incorrectly interpreted as functionally tight, are actually very leaky and probably contribute only to the structural stability of the myelin sheath architecture.     

Retention of a cell adhesion complex at the paranodal junction requires the cytoplasmic region of Caspr

An axonal complex of cell adhesion molecules consisting of Caspr and contactin has been found to be essential for the generation of the paranodal axo-glial junctions flanking the nodes of Ranvier. Here we report that although the extracellular region of Caspr was sufficient for directing it to the paranodes in transgenic mice, retention of the Caspr-contactin complex at the junction depended on the presence of an intact cytoplasmic domain of Caspr. Using immunoelectron microscopy, we found that a Caspr mutant lacking its intracellular domain was often found within the axon instead of the junctional axolemma. We further show that a short sequence in the cytoplasmic domain of Caspr mediated its binding to the cytoskeleton-associated protein 4.1B. Clustering of contactin on the cell surface induced coclustering of Caspr and immobilized protein 4.1B at the plasma membrane. Furthermore, deletion of the protein 4.1B binding site accelerated the internalization of a Caspr-contactin chimera from the cell surface. These results suggest that Caspr serves as a "transmembrane scaffold" that stabilizes the Caspr/contactin adhesion complex at the paranodal junction by connecting it to cytoskeletal components within the axon.     

Ultrastructure of the Squid Axon Membrane as Revealed by Freeze-Fracture Electron Microscopy

The structure of the axolemma of the squid giant axon was studied by freeze-fracture electron microscopy. Three types of preparations were examined: intact axons, axons with their Schwann cell sheaths stripped off prior to freezing, and axons with their Schwann cell sheaths chemically detached but not mechanically removed. Because of a problem of cross-fracturing, the first two types of preparations revealed very few membrane faces of the axolemma. This cross-fracturing problem, however, was eliminated when we used a complementary replication method to fracture the third type of preparation. We found that the E-face of the axon membrane was smooth relative to the P-face, which showed many prominent intramembrane particles (IMP). The diameters of the typical IMP range from 6 to 15 nm. The P-face of the adjacent Schwann cells also showed many large IMP. The sizes and heights of the Schwann-cell IMP, however, appear to be more homogeneous than the P-face axolemma.     

Molecular mechanisms of node of Ranvier formation

Action potential propagation along myelinated nerve fibers requires high-density protein complexes that include voltage-gated Na(+) channels at the nodes of Ranvier. Several complementary mechanisms may be involved in node assembly including: (1) interaction of nodal cell adhesion molecules with the extracellular matrix; (2) restriction of membrane protein mobility by paranodal junctions; and (3) stabilization of ion channel clusters by axonal cytoskeletal scaffolds. In the peripheral nervous system, a secreted glial protein at the nodal extracellular matrix interacts with axonal cell adhesion molecules to initiate node formation. In the central nervous system, both glial soluble factors and paranodal axoglial junctions may function in a complementary manner to contribute to node formation.     

The developing cervical spinal ventral commissure of the rat: A highly controlled axon-glial system

The floor plate of the neural tube is of major importance in determining axonal behaviour, such that, having crossed, decussating axons do not cross back again. The ventral commissure (VC) of the spinal cord forms immediately ventral to the floor plate shortly after neural tube closure. It is the principal location in which decussating axons cross the midline. It is probably also of major importance in neural tube development, but has received relatively little attention. This study analyses the growth and development of the rat VC and also axon-glial relationships within it throughout the crucial prenatal period of extensive transmedian axon growth, when key biochemical interactions between the two tissues are taking place. The morphometric, stereological and immunohistochemical methods used show that the axonal and glial populations remain in a finely balanced equilibrium throughout a period of almost a hundred-fold growth of both elements. At all stages axons are highly segregated into small bundles of constant size by glial processes, to which they are closely apposed. Thus, glial-axon contact is remarkably precocious, uniquely intimate and persists throughout VC development. This suggests that the relationship between the two tissues is highly controlled through interactions between them. The VC is likely to be the physical basis of a second set of glial-axonal interactions, namely, those which are well known to influence axon crossing behaviour. In mediating these, the extensive axon-glial contact is an ideal arrangement for molecular transfer between them, and is probably the substrate for altering axon responsiveness and ensuring reliable transmedian decussation. The VC is therefore a segregating matrix temporally and spatially specialised for a range of key developmental axon-glial interactions.     

On the molecular architecture of myelinated fibers

Schwann cells and oligodendrocytes make the myelin sheaths of the PNS and CNS, respectively. Their myelin sheaths are structurally similar, consisting of multiple layers of specialized cell membrane that spiral around axons, but there are several differences. (1) CNS myelin has a ”radial component” composed of a tight junction protein, claudin-11/oligodendrocyte-specific protein. (2) Schwann cells have a basal lamina and microvilli. (3) Although both CNS and PNS myelin sheaths have incisures, those in the CNS lack the structural as well as the molecular components of ”reflexive” adherens junctions and gap junctions. In spite of their structural differences, the axonal membranes of the PNS and CNS are similarly organized. The nodal axolemma contains high concentrations of voltage-dependent sodium channels that are linked to the axonal cytoskeleton by ankyrin_G. The paranodal membrane contains Caspr/paranodin, which may participate in the formation of axoglial junctions. The juxtaparanodal axonal membrane contains the potassium channels Kv1.1 and Kv1.2, their associated β2 subunit, as well as Caspr2, which is closely related to Caspr. The myelin sheath probably organizes these axonal membrane-related proteins via trans interactions. Accepted: 25 November 1999     

Cellular contacts in myelinated fibers of the peripheral nervous system

Myelination allows the fast propagation of action potentials at a low energetic cost. It provides an insulating myelin sheath regularly interrupted at nodes of Ranvier where voltage-gated Na+ channels are concentrated. In the peripheral nervous system, the normal function of myelinated fibers requires the formation of highly differentiated and organized contacts between the myelinating Schwann cells, the axons and the extracellular matrix. Some of the major molecular complexes that underlie these contacts have been identified. Compact myelin which forms the bulk of the myelin sheath results from the fusion of the Schwann cell membranes through the proteins P0, PMP22 and MBP. The basal lamina of myelinating Schwann cells contains laminin-2 which associates with the glial complex dystroglycan/DPR2/L-periaxin. Non compact myelin, found in paranodal loops, periaxonal and abaxonal regions, and Schmidt-Lanterman incisures, presents reflexive adherens junctions, tight junctions and gap junctions, which contain cadherins, claudins and connexins, respectively. Axo-glial contacts determine the formation of distinct domains on the axon, the node, the paranode, and the juxtaparanode. At the paranodes, the glial membrane is tightly attached to the axolemma by septate-like junctions. Paranodal and juxtaparanodal axoglial complexes comprise an axonal transmembrane protein of the NCP family associated in cis and in trans with cell adhesion molecules of the immunoglobulin superfamily (IgSF-CAM). At nodes, axonal complexes are composed of Na+ channels and IgSF-CAMs. Schwann cell microvilli, which loosely cover the node, contain ERM proteins and the proteoglycans syndecan-3 and -4. The fundamental role of the cellular contacts in the normal function of myelinated fibers has been supported by rodent models and the detection of genetic alterations in patients with peripheral demyelinating neuropathies such as Charcot-Marie-Tooth diseases. Understanding more precisely their molecular basis now appears essential as a requisite step to further examine their involvement in the pathogenesis of peripheral neuropathies in general.     

The Axonal Membrane Protein Caspr, a Homologue of Neurexin IV, Is a Component of the Septate-like Paranodal Junctions That Assemble during Myelination

We have investigated the potential role of contactin and contactin-associated protein (Caspr) in the axonal–glial interactions of myelination. In the nervous system, contactin is expressed by neurons, oligodendrocytes, and their progenitors, but not by Schwann cells. Expression of Caspr, a homologue of Neurexin IV, is restricted to neurons. Both contactin and Caspr are uniformly expressed at high levels on the surface of unensheathed neurites and are downregulated during myelination in vitro and in vivo. Contactin is downregulated along the entire myelinated nerve fiber. In contrast, Caspr expression initially remains elevated along segments of neurites associated with nascent myelin sheaths. With further maturation, Caspr is downregulated in the internode and becomes strikingly concentrated in the paranodal regions of the axon, suggesting that it redistributes from the internode to these sites. Caspr expression is similarly restricted to the paranodes of mature myelinated axons in the peripheral and central nervous systems; it is more diffusely and persistently expressed in gray matter and on unmyelinated axons. Immunoelectron microscopy demonstrated that Caspr is localized to the septate-like junctions that form between axons and the paranodal loops of myelinating cells. Caspr is poorly extracted by nonionic detergents, suggesting that it is associated with the axon cytoskeleton at these junctions. These results indicate that contactin and Caspr function independently during myelination and that their expression is regulated by glial ensheathment. They strongly implicate Caspr as a major transmembrane component of the paranodal junctions, whose molecular composition has previously been unknown, and suggest its role in the reciprocal signaling between axons and glia.     

Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/Paranodin

Myelinated fibers are organized into distinct domains that are necessary for saltatory conduction. These domains include the nodes of Ranvier and the flanking paranodal regions where glial cells closely appose and form specialized septate-like junctions with axons. These junctions contain a Drosophila Neurexin IV-related protein, Caspr/Paranodin (NCP1). Mice that lack NCP1 exhibit tremor, ataxia, and significant motor paresis. In the absence of NCP1, normal paranodal junctions fail to form, and the organization of the paranodal loops is disrupted. Contactin is undetectable in the paranodes, and K(+) channels are displaced from the juxtaparanodal into the paranodal domains. Loss of NCP1 also results in a severe decrease in peripheral nerve conduction velocity. These results show a critical role for NCP1 in the delineation of specific axonal domains and the axon-glia interactions required for normal saltatory conduction.