Single Schwann Cell Research Articles

Label-free real-time imaging of myelination in the Xenopus laevis tadpole by in vivo stimulated Raman scattering microscopy.

The myelin sheath plays an important role as the axon in the functioning of the neural system, and myelin degradation is a hallmark pathology of multiple sclerosis and spinal cord injury. Electron microscopy, fluorescent microscopy, and magnetic resonance imaging are three major techniques used for myelin visualization. However, microscopic observation of myelin in living organisms remains a challenge. Using a newly developed stimulated Raman scattering microscopy approach, we report noninvasive, label-free, real-time in vivo imaging of myelination by a single-Schwann cell, maturation of a single node of Ranvier, and myelin degradation in the transparent body of the Xenopus laevis tadpole.

Lysophosphatidic acid (LPA) and its receptor, LPA1, influence embryonic schwann cell migration, myelination, and cell-to-axon segregation

Schwann cell (SC) migration is an important step preceding myelination and remyelination in the peripheral nervous system, and can be promoted by peptide factors like neuregulins. Here we present evidence that a lipid factor, lysophosphatidic acid (LPA), influences both SC migration and peripheral myelination through its cognate G protein-coupled receptor (GPCR) known as LPA1 . Ultrastructural analyses of peripheral nerves in mouse null-mutants for LPA1 showed delayed SC-to-axon segregation, polyaxonal myelination by single SCs, and thinner myelin sheaths. In primary cultures, LPA promoted SC migration through LPA1 , while analysis of conditioned media from purified dorsal root ganglia neurons using HPLC/MS supported the production of LPA by these neurons. The heterotrimeric G-alpha protein, Gαi , and the small GTPase, Rac1, were identified as important downstream signaling components of LPA1 . These results identify receptor mediated LPA signaling between neurons and SCs that promote SC migration and contribute to the normal development of peripheral nerves through effects on SC-axon segregation and myelination.

Neuronal Neuregulin 1 type III directs Schwann cell migration

During peripheral nerve development, each segment of a myelinated axon is matched with a single Schwann cell. Tight regulation of Schwann cell movement, proliferation and differentiation is essential to ensure that these glial cells properly associate with axons. ErbB receptors are required for Schwann cell migration, but the operative ligand and its mechanism of action have remained unknown. We demonstrate that zebrafish Neuregulin 1 (Nrg1) type III, which signals through ErbB receptors, controls Schwann cell migration in addition to its previously known roles in proliferation and myelination. Chimera analyses indicate that ErbB receptors are required in all migrating Schwann cells, and that Nrg1 type III is required in neurons for migration. Surprisingly, expression of the ligand in a few axons is sufficient to induce migration along a chimeric nerve constituted largely of nrg1 type III mutant axons. These studies also reveal a mechanism that allows Schwann cells to fasciculate axons regardless of nrg1 type III expression. Time-lapse imaging of transgenic embryos demonstrated that misexpression of human NRG1 type III results in ectopic Schwann cell migration, allowing them to aberrantly enter the central nervous system. These results demonstrate that Nrg1 type III is an essential signal that controls Schwann cell migration to ensure that these glia are present in the correct numbers and positions in developing nerves.

Non-redundant function of dystroglycan and β1 integrins in radial sorting of axons

Radial sorting allows the segregation of axons by a single Schwann cell (SC) and is a prerequisite for myelination during peripheral nerve development. Radial sorting is impaired in models of human diseases, congenital muscular dystrophy (MDC) 1A, MDC1D and Fukuyama, owing to loss-of-function mutations in the genes coding for laminin α2, Large or fukutin glycosyltransferases, respectively. It is not clear which receptor(s) are activated by laminin 211, or glycosylated by Large and fukutin during sorting. Candidates are αβ1 integrins, because their absence phenocopies laminin and glycosyltransferase deficiency, but the topography of the phenotypes is different and β1 integrins are not substrates for Large and fukutin. By contrast, deletion of the Large and fukutin substrate dystroglycan does not result in radial sorting defects. Here, we show that absence of dystroglycan in a specific genetic background causes sorting defects with topography identical to that of laminin 211 mutants, and recapitulating the MDC1A, MDC1D and Fukuyama phenotypes. By epistasis studies in mice lacking one or both receptors in SCs, we show that only absence of β1 integrins impairs proliferation and survival, and arrests radial sorting at early stages, that β1 integrins and dystroglycan activate different pathways, and that the absence of both molecules is synergistic. Thus, the function of dystroglycan and β1 integrins is not redundant, but is sequential. These data identify dystroglycan as a functional laminin 211 receptor during axonal sorting and the key substrate relevant to the pathogenesis of glycosyltransferase congenital muscular dystrophies.

Developmental changes in the ultrastructure of the lamprey lateral line nerve during metamorphosis

The ultrastructure of the trunk lateral line nerve of larval and adult lampreys was studied with transmission electron microscopy. We confirmed that lampreys' lateral line nerve lacks myelin. Nevertheless, all axons were wrapped by Schwann cell processes. In the larval nerve, gaps between Schwann cells were observed, where the axolemma was covered only by a basal lamina, indicating an earlier developmental stage. In the adult nerve, glial (Schwann cell) ensheathment was mostly complete. Additionally, we observed variable ratios of axons to Schwann cells in larval and adult preparations. In the larval nerve, smaller axons were wrapped by one Schwann cell. Occasionally, a single Schwann cell surrounded two axons. Larger axons were associated with two to five Schwann cells. In the adult nerve, smaller axons were surrounded by one, but larger axons by three to eight Schwann cells. The larval epineurium contained large adipose cells, separated from each other by single fibroblast processes. This layer of adipose tissue was reduced in adult preparation. The larval perineurium was thin, and the fibroblasts, containing large amounts of glycogen granules, were arranged loosely. The adult perineurium was thicker, consisting of at least three layers of fibroblasts separated by collagen fibrils. The larval and adult endoneurium contained collagen fibrils oriented orthogonally to each other. Both larval and adult lateral line nerves possessed a number of putative fascicles weakly defined by a thin layer of perineurial fibroblasts. These results indicate that after a prolonged larval stage, the lamprey lateral line nerve is subjected to additional maturation processes during metamorphosis.

Defective peripheral nerve myelination and neuromuscular junction formation in fukutin‐deficient chimeric mice

Dystroglycan is a central component of the dystrophin-glycoprotein complex that links the extracellular matrix with cytoskeleton. Recently, mutations of the genes encoding putative glycosyltransferases were identified in several forms of congenital muscular dystrophies accompanied by brain anomalies and eye abnormalities, and aberrant glycosylation of alpha-dystroglycan has been implicated in their pathogeneses. These diseases are now collectively called alpha-dystroglycanopathy. In this study, we demonstrate that peripheral nerve myelination is defective in the fukutin-deficient chimeric mice, a mouse model of Fukuyama-type congenital muscular dystrophy, which is the most common alpha-dystroglycanopathy in Japan. In the peripheral nerve of these mice, the density of myelinated nerve fibers was significantly decreased and clusters of abnormally large non-myelinated axons were ensheathed by a single Schwann cell, indicating a defect of the radial sorting mechanism. The sugar chain moiety and laminin-binding activity of alpha-dystroglycan were severely reduced, while the expression of beta1-integrin was not altered in the peripheral nerve of the chimeric mice. We also show that the clustering of acetylcholine receptor is defective and neuromuscular junctions are fragmented in appearance in these mice. Expression of agrin and laminin as well as the binding activity of alpha-dystroglycan to these ligands was severely reduced at the neuromuscular junction. These results demonstrate that fukutin plays crucial roles in the myelination of peripheral nerve and formation of neuromuscular junction. They also suggest that defective glycosylation of alpha-dystroglycan may play a role in the impairment of these processes in the deficiency of fukutin.

Localization of E-cadherin in peripheral glia after nerve injury and repair.

Peripheral nerve injury results in histological and histochemical changes in neurons and glia. We have recently found that Ca(2+)-dependent cell adhesion molecule E-cadherin plays an important role in the selective fasciculation of a particular subset of unmyelinated sensory fibers. In the present immunohistochemical and immunoblot analyses, the temporal profile of the subcellular expression of this molecule in spinal nerves was examined after crushing, transecting, or ligaturing the sciatic nerve in mice with special attention paid to E-cadherin expression in glial cells. After axotomy of the sciatic nerve, distal axons of the proximal stump and the fibers of the distal stump degenerated, but E-cadherin was still detectable at the outer mesaxons of the myelinated axons as long as they remained morphologically intact. Subsequently, Schwann cells proliferated and migrated to form Schwann cell columns (Büngner's bands) as initial responses to denervation, and expressed E-cadherin at their site of contact with each other and later with sprouting axons. At the initial stage of myelin formation, slender processes of a single Schwann cell interdigitated with an enveloped axons, and expressed E-cadherin at the contact site elaborated by a single Schwann cell. Immunoblot analysis on day 7 revealed that E-cadherin was detected in both the proximal nerve segments and the regenerative distal segments, but was negative in the degenerative distal segments. On the basis of present data, it is suggested that E-cadherin might be involved in the stabilization of the peripheral glial network which provides the guidance of sprouting axons and myelination.

Novel E-cadherin-mediated adhesion in peripheral nerve: Schwann cell architecture is stabilized by autotypic adherens junctions.

Previous studies (Blank, W. F., M. B. Bunge, and R. P. Bunge. 1974. Brain Res. 67:503-518) showed that Schwann cell paranodal membranes were disrupted in calcium free medium suggesting that cadherin mediated mechanisms may operate to maintain the integrity of the paranodal membrane complex. Using antibodies against the fifth extracellular domain of E-cadherin, we now show by confocal laser and electron immunomicroscopy that E-cadherin is a major adhesive glycoprotein in peripheral nervous system Schwann cells. E-Cadherin is not found, however, in compact myelin bilayers. Rather, it is concentrated at the paranodes, in Schmidt-Lanterman incisures, and at the inner and outer loops. At these loci, E-cadherin is associated with subplasmalemmal electron densities that coordinate in register across several cytoplasmic turns of a single Schwann cell. F-Actin and beta-catenin, two proteins implicated in cellular signaling, also co-localize to E-cadherin positive sites. These complexes are autotypic adherens-type junctions that are confined to the plasma membrane synthesized by a single Schwann cell; E-cadherin was never observed between two Schwann cells, nor between Schwann cells and the axon. Our findings demonstrate that E-cadherin and its associated proteins are essential components in the architecture of the Schwann cell cytoplasmic channel network, and suggest that this network has specialized functions in addition to those required for myelinogenesis.

Vagal nerve maturation in the fetal lamb: an ultrastructural and morphometric study.

The maturation of the left vagal nerve was studied in the fetal lamb by transmission electron microscopy and by computer-assisted morphometry of sections of the entire nerve at seven gestational ages between 79 and 145 days (term is 147 days) and in the adult ewe. The number of unmyelinated axons per Schwann cell progressively decreased from 25 to 55 at 79 days to 1 to 5 at near-term. Unmyelinated axons of various sizes were enclosed within a single Schwann cell at all ages, but the mean axonal diameter increased in inverse relation to the number of unmyelinated axons. A few Schwann cells enclosed two myelinated axons, but in most instances myelination did not begin until a 1:1 ratio was achieved; some single axons with a Schwann cell remained unmyelinated in the adult. Myelinated fibers were rare at 79 days but myelination progressed rapidly thereafter until the adult ratio of myelinated: unmyelinated fibers was reached at about 100 days; myelinated axons were not uniformly distributed. The myelin sheaths and axons of small fibers progressively increased in diameter in late gestation, but new large fibers were not added. Early myelinating fibers and immature unmyelinated axons contained more microtubules than neurofilaments; neurofilaments predominated in mature axons with or without myelin. Cross-linkages between neurofilaments were already evident by 79 days. Maturation of the vagal nerve thus occurs first by an increase in number of myelinated fibers and then by an increase in the size of each fiber in this fixed population. The bimodal distribution in the size histogram of myelinated fibers is not achieved until 134 days gestation and correlates well with physiological maturation of respiratory patterns.

Internodal microvilli of Schwann cells of myelinated fibres in lizard spinal roots project onto unmyelinated axons.

Tufts of microvilli originating from the internodal cytoplasm of Schwann cells associated with myelinated axons in apparently normal lizard spinal roots have been studied under the electron microscope by means of both single and serial sections. More than one tuft of internodal microvilli may arise from a single Schwann cell. Sometimes mitochondria and more frequently an organelle resembling a multivesicular body with a clear matrix can be found in the Schwann cell cytoplasm underlying a tuft of internodal microvilli. The dimensions (length: 0.4-1.0 microns; diameter: 40-70 nm) and structure of internodal microvilli of the Schwann cell are very similar to those of nodal microvilli of the same cell. Each tuft of internodal microvilli projects towards an adjacent unmyelinated axon which at this site is partly devoid of its own Schwann cell sheath. Thus a single Schwann cell may be related to a myelinated axon and an unmyelinated axon at the same time. Patches of a dense axolemmal undercoating (which could be portions of the cytoskeleton) are present in the unmyelinated axon in close spatial correlation with internodal microvilli. The factors which could induce the formation of internodal microvilli as well as the possible role (or roles) of these microvilli are briefly discussed.

Double myelination of axons in the sympathetic nervous system of the mouse. I. Ultrastructural features and distribution.

This study has examined the structural features and distribution of 'doubly myelinated' axons in normal adult and aged mice. Investigation focused on the superior cervical ganglion (SCG) and paravertebral sympathetic ganglia, which were extensively serial-sectioned for light and electron microscopy. In the SCG, the principal features of doubly myelinated regions were that an apparently normal myelinated axon was enclosed for part of its length by an additional (outer) myelinating Schwann cell. The separate nature of the inner and outer Schwann cells was emphasized by the consistent presence of individual nuclei in each, and by the presence of endoneurial space, often containing collagen fibrils, between the inner and outer cells. In some cases more than a single outer Schwann cell was present, arranged serially along the inner myelinated fibre. While double myelination forms through a mechanism involving displacement of an original myelinating Schwann cell by an interposed Schwann cell (see companion paper), we here provide evidence that in some instances the outer Schwann cell fails to retain any direct axonal contact, either with the axon centrally enclosed within the configuration or with any neighbouring axon. In contrast to the rat, delicate cytoplasmic processes often extended from the lateral extremes of outer Schwann cells. However, again no evidence for axonal contact was found, and similar processes also extended from the paranodal region of some singly myelinated non-displaced Schwann cells. Without exception the outer myelin sheath remained structurally intact, and characteristically underwent a series of conformational changes (progressive infolding of the paranodes and new areas of myelin compaction) which infer a continuing capacity of the outer Schwann cell to translocate myelin-specific components in a co-ordinated manner. A basal lamina was always present on the 'abaxonal' plasma membrane of the outer cell, but not on the 'adaxonal' surface except in areas involved in infolding, thus retaining the polarity which existed at the time of displacement from the axon. At single cross-sectional levels through the SCG, up to approximately 4% of myelinated axons were involved in double myelination. Double myelination was not detected in the sciatic nerve or in the paravertebral ganglia, thus indicating a predilection for the SCG as a site of development of these configurations. Though not challenging the role of the axon in initiating the formation of myelin, these data indicate that in this tissue myelin maintenance does not require direct contact between axonal and Schwann cell plasma membranes.

Development of the spinal nerves of the larval lamprey: IV. Spinal nerve roots of 21-mm larval and adult lampreys, with special reference to the relation of meninges with the root sheath and the perineurium.

Spinal nerve roots of 21-mm larval and adult lampreys were electron microscopically studied. In 21-mm larval lampreys, each ventral and dorsal rootlet contains axons of various diameters enclosed together as groups in individual troughs of a Schwann cell cytoplasm, lying in direct contact with one another, and is further ensheathed entirely by a basal lamina. Dorsal roots possess visceral axons, while ventral roots lack them. In adult lampreys the ventral and dorsal roots possess individual sheaths for larger somatic axons, each being surrounded by a single Schwann cell and the basal lamina and separated from one another by a considerable amount of connective tissue. Visceral fibers are present in both the dorsal and ventral roots of adult lampreys. They aggregate to form fascicles that lie among somatic axons, being separated from them. Two layers of the meningeal tissue invaginate to form a root sheath around the distal portion of individual dorsal and ventral roots of 21-mm larval lampreys. In adult lampreys the sheath is similarly formed but extends over most of the dorsal and ventral roots. The perineurium is not developed in 21-mm larval lampreys, but is present and ensheaths only the proximal portion of spinal nerve trunks outside the meninges in adult lampreys: it is completely absent along most of the length of peripheral nerves. In both larval and adult lampreys, the outer cell layer of the root sheath is open-ended near the middle of nerve roots with respect to the extramedullary connective tissue space. Similar loosening of the cellular barrier is seen along blood vessels. Thus, the outer meningeal fibrous layer is directly continuous with the extra medullary connective tissue space by way of the inner fibrous layer of the root sheath.

Naked axon bundles enclosed by single segments of myelin sheaths in the nerves of non-dystrophic C57BL-ob/+mice.

Bundles of axons enclosed by a single myelin sheath were found in the peripheral nerves of heterozygous obese C57BL-ob/+mice. Serial sections showed them to consist of two to forty naked axons encompassed by a common cuff of myelin formed by a single Schwann cell, with adjoining non-myelinated Schwann cells protruding from either side into the cuff. These structures are similar to those found in dystrophic mice, but there were no signs of dystrophy in the obese mice. It is suggested that the axon bundles result from a disturbance of early myelination, presumably of the phase of Schwann cell proliferation or of the communication between Schwann cells and axons.

Immunocytochemical localization of the myelin-associated glycoprotein Fact or Artifact?

Immune staining for the myelin-associated glycoprotein (MAG) by the peroxidase-antiperoxidase technique in vibratome, paraffin and Epon sections of peripheral nerve resulted in a periaxonal ring of immune reaction product and an absence of staining over compact myelin. The thicknesses of the periaxonal rings of staining in Epon sections were similar when axons were surrounded by single Schwann cell processes and when they were surrounded by compact myelin sheats. Thicker rings of periaxonal staining were present when axons were surrounded by multiple layers of uncompacted Schwann cell membranes. When swelling of the Schwann cell periaxonal cytoplasm separated the periaxonal Schwann cell membrane from compact myelin by distances that could be readily resolved in the light microscope, immune staining for MAG was found over the periaxonal Schwann cell membrane but not over compact myelin. Biochemical experiments in which myelin or MAG was treated with sodium ethoxide and hydrogen peroxide, under conditions similar to those used for etching Epon sections prior to immune staining, showed that the immune reactivity of MAG was stable to these treatments. Finally, a pre-embedding technique for immune staining at the electron-microscopic level showed MAG reaction product on the cytoplasmic side of Schwann cell periaxonal membranes and the membranes of Schmidt-Lanterman incisures and paranodal loops. These results confirm and strengthen the evidence from previous reports indicating that MAG is confined to periaxonal membranes, Schmidt-Lanterman incisures, paranodal loops, and the outer mesaxon of myelinating Schwann cells and is absent from compact myelin. These results are discussed in reference to a recent report apparently showing the presence of MAG in compact CNS myelin. Based on the data presented and discussed in this paper, it is concluded that MAG is located in specific non-compact regions of central and peripheral myelin sheaths and not in compact myelin lamellae.

Occurrence of long non-myelinated axonal segments intercalated in myelinated, presumably sensory axons: electron microscopic observations in the dog atrial endocardium.

Electron microscopy of serial sections revealed the occurrence of long non-myelinated segments in myelinated, presumably sensory axons running in the left atrial endocardium of normal adult dogs. Four such non-myelinated segments were analysed in three myelinated axons. They varied from 20 to 150 microns in length, and differed from nodes of Ranvier in being invested by Schwann cells in the manner of unmyelinated nerve fibers. Short non-myelinated portions (20-25 microns long) were associated with a single Schwann cell, whereas the longest such segment (150 microns) had five. The non-myelinated axonal segments were non-varicose and similar in diameter (1.2-3.0 microns) to adjacent myelinated segments, which had myelin sheaths 6-25 lamellae thick. The cytoplasm of the non-myelinated axonal segments contained numerous neurofilaments and microtubules, some mitochondria and smooth endoplasmic reticulum. The short non-myelinated segments were enclosed by perineurium, whereas the long non-myelinated segment was devoid of perineurium at its mid-portion; instead fibroblast-like cells made a loose boundary around the axon at this level. The significance of these non-myelinated segments was discussed with special emphasis on the question of whether they result from focal degeneration of the myelin sheath (demyelination) or are generally present in the preterminal regions of some axons.

Changes in the compact myelin of single internodes during axonal atrophy.

Distal axonal atrophy was produced by proximal constriction of the tibial nerve in the rabbit. Transverse sections were studied by light and electron microscopy at 10 micron intervals along individual internodes of both atrophic and normal tibial nerve fibres. During axonal atrophy there were marked changes in axonal configuration at different levels within the territory of a single Schwann cell. These resulted in changes in the lengths of the axon perimeter and myelin spiral, without causing any alteration in the numbers of myelin lamellae or their spacing. Comparable changes in axon perimeter and myelin spiral length were seen in transverse sections through the paranodal and nuclear regions of normal fibres. These results show that local variations in axonal calibre or shape are associated with appropriate adjustments to the length of the myelin spiral, without a change in the number of lamellae, and thus of sheath thickness.

Regeneration of olfactory sensory axons into transplanted segments of peripheral nerve

Isolated segments of cervical sympathetic trunk were transplanted onto the olfactory mucosa and bulb in adult rats, and olfactory nerve fascicles were sectioned in the region of the transplant. Olfactory axons, presumably arising from newly-formed sensory neurons, were observed to grow into the transplanted segments of peripheral nerve and were ensheathed by Schwann cells of the transplant. The axons were ensheathed as large bundles containing many axons in direct contact, an arrangement characteristic of the normal olfactory nerves, and not of the normal sympathetic trunk. However, single Schwann cell ‘units’ were each surrounded by basal lamina, an arrangement typical of the sympathetic trunk, not of olfactory nerves. The results indicate that olfactory axons, like other peripheral axons, are capable of directing some aspects of the manner in which they are ensheathed by Schwann cells.

The development of rat dorsal root ganglia in three experimental media containing Landry-Guillain-Barré, alcoholic peripheral neuropathy or normal adult sera.

Development of rat dorsal root ganglia in vitro mimics the development of rat dorsal root ganglia in vivo when grown in medium containing human cord serum. When serum from patients either in the acute phase of Landry-Guillain-Barré syndrome or with alcoholic peripheral neuropathy is substituted for human cord serum, maturation is inhibited. Development of fetal relationships occurs between the Schwann cells and axons and many axons become enclosed within the processes of a single Schwann cell. Formation of myelin does not occur. The substitution of normal adult blood for cord serum also inhibits maturation, but unlike development with neuropathic serum, the Schwann cells and axons do not become associated and myelination does not occur.

Growth of a limb spinal nerve: an ultrastructural study.

A quantitative study of the delivery of nerve fibres to the developing limb has been made. Electron microscope (EM) sections of SN 9 in Xenopus were taken at close intervals between dorsal root ganglion and limb-bud. Numbers and types of axons in each section were counted. Counts declined steadily with distance from the ganglion towards the base of the limb. This is large due to some axons not having grown the full distance at the time of fixation. The slope corresponded with an outgrowth velocity of 0.5 mm a day, without branching. Distally, at stages 50 and 51, but not at stages 49 and 54, the decline was reversed, and a peak of axon number was found. This is strong evidence for axon branching in this region. Since this took place at least one stage before SN 9 bifurcated, and since the bifurcation was distal to the branching when it did appear, it is suggested that axon branching at a nerve bifurcation might be part of a trial-and-error mechanism for pathway selection. Observations were made on the sheath surrounding the nerve, and on its assembly. Initially, axons grow out naked and not parallel; Schwann cells migrate after the growing front. Processes of these cells collect individual axons, and transfer them inwards to form the primitive parallel fibre bundle, enclosed by a family of Schwann cells. Myelination later occurs in a similar manner: Schwann-cell processes extend into a bundle of naked axons and eventually encircle a single transitional axon, with one Schwann cell eventually containing many such axons. Finally comes the stage of promyelin, in which a single Schwann cell encircles a single axon. Myelin whorls are then formed from this complex.

Atypical axon-Schwann cell relationships in the common peroneal nerve of the dystrophic mouse: an ultrastructural study.

Several atypical features of myelination of the peripheral nervous system are reported in common peroneal nerve of dystrophic mice (129 Re J dy/dy): (i) central nervous system-like contact between myelin sheaths of adjacent nerve fibres; (ii) nodes and internodes of myelinated fibres enwrapped with cytoplasmic processes of Schwann cells from adjacent nerve fibres; (iii) Schwann cells of adjacent nerve fibres co-operating in formation of a single myelin sheath; and (iv) a single Schwann cell myelinating two separate axons. In view of the presence of similar features of myelination in the central nervous system, where the myelin producing cells lack basement membrane, we suggest that in the dystrophic peripheral nerves the development of these features can be attributed to the partial deficiency of the Schwann cell basement membrane. Two types of widened nodes of Ranvier are also identified: (i) nodes with paranodal damage; and (ii) nodes without paranodal damage. In addition, abnormal features of myelination are described which are likely to represent altered Schwann cell/axon relationships during demyelination and remyelination and/or decreased myelinating ability of Schwann cells. We interpret these findings as indicating a metabolic disorder of Schwann cells. They provide an experimental model for the investigation of factors involved in the origin and maintenance of the structural organization of peripheral nerve.