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PubMed1993

Immunoelectronmicroscopical demonstration of major histocompatibility class II antigen: expression on endothelial and perivascular cells but not Schwann cells in human neuropathy.

A pre-embedding technique for identifying major histocompatibility (MHC) class II antigen with monoclonal antibody LN3 at the electron microscope level by immunogold silver enhancement was applied to sections from 12 human nerve biopsies. Many perivascular mononuclear cells in the epineurium, perineurium and endoneurium expressed MHC class II antigen and had the morphological appearance of macrophages. Cell processes expressing MHC class II antigen extended throughout the endoneurium, often close to Schwann cells. No MHC class II expression was identified on myelinating or non-myelinating Schwann cells. The endothelial cells of epineurial blood vessels expressed MHC class II antigen on their luminal surfaces more often and more strongly than those of the endoneurial vessels. These observations indicate that perivascular cells in both the endoneurium and perineurium commonly express the molecules necessary to present antigen to CD4+ T lymphocytes, but Schwann cells do not.

Adult↗

PubMed1993

Changes in DNA synthesis rate in the Schwann cell lineage in vivo are correlated with the precursor--Schwann cell transition and myelination.

During the development of the rat sciatic nerve extensive proliferation of glial cells occurs, and there is a very substantial rearrangement of the cytoarchitecture as axons and Schwann cells assume relationships which lead to the formation of the myelinated and unmyelinated axons characteristic of adult nerve. The maturation of Schwann cells from Schwann cell precursors and the matching of Schwann cell numbers to axons is an important part of this process. We have therefore studied the proliferation of Schwann cell precursors and Schwann cells during the development of the rat sciatic nerve from embryonic day 14 to postnatal day 28 by combining bromodeoxyuridine injections of rats with double-label immunohistochemical techniques. The results reveal that DNA synthesis occurs in both Schwann cell precursors and Schwann cells throughout early nerve development. The labelling index is already substantial at embryonic day 14, but from embryonic day 17, when essentially all the glial cells have converted from precursor to Schwann cell phenotype, it rises sharply, peaking between embryonic day 19 and 20 before declining precipitously in the early postnatal period. This rapid decline in DNA synthesis coincides with the appearance of the myelin protein P0, and in individual cells DNA synthesis is incompatible with the expression of P0 protein. Nonmyelin-forming Schwann cells, which mature later in development, continue to synthesize DNA until at least postnatal day 15, but by day 28 essentially all Schwann cells in the nerve are quiescent.

Animals↗

PubMed2006

Glypican-1 and alpha4(V) collagen are required for Schwann cell myelination.

Schwann cell myelination requires interactions with the extracellular matrix (ECM) mediated by cell surface receptors. Previously, we identified a type V collagen family member, alpha4(V) collagen, which is expressed by Schwann cells during peripheral nerve differentiation. This collagen binds with high affinity to heparan sulfate through a unique binding motif in the noncollagenous N-terminal domain (NTD). The principal alpha4(V) collagen-binding protein on the Schwann cell surface is the heparan sulfate proteoglycan glypican-1. We investigated the role of alpha4(V) collagen and glypican-1 in Schwann cell terminal differentiation in cultures of Schwann cells and dorsal root ganglion neurons. Small interfering RNA-mediated suppression of glypican-1 expression decreased binding of alpha4(V)-NTD to Schwann cells, adhesion and spreading of Schwann cells on alpha4(V)-NTD, and incorporation of alpha4(V) collagen into Schwann cell ECM. In cocultures, alpha4(V) collagen coassembles with laminin on the surface of polarized Schwann cells to form tube-like ECM structures that are sites of myelination. Suppression of glypican-1 or alpha4(V) collagen expression significantly inhibited myelination. These results demonstrate an important role for these proteins in peripheral nerve terminal differentiation.

Animals↗

PubMed1998

Ionic currents in normal and neurofibromatosis type 1-affected human Schwann cells: induction of tumor cell K current in normal Schwann cells by cyclic AMP.

Comparisons were made of whole cell voltage clamp recordings from cultures of normal Schwann cells (SC) from three human subjects and from three neurofibrosarcoma cell lines. The whole cell K+ (K) currents of normal and tumor cells could be divided into three types based on voltage activation range, pharmacology, and macroscopic inactivation: A type current, tetraethylammonium- (TEA-) only-sensitive current, and inward rectifier current. The most conspicuous difference between normal and tumor cells was the nature of K currents present. Normal SC K currents were inactivating, A type currents blocked by extracellular 4-aminopyridine (4-AP; 5 mM). The whole cell K currents of tumor cells were noninactivating due to the presence of non-inactivating A current, or non-inactivating, TEA-only sensitive current, or both, despite the presence of inactivating A current in some tumor cells. TEA-only-sensitive currents, which were 4-AP-insensitive and noninactivating, were common in all three tumor cell lines, but were not observed in normal SC. Inward rectifier K currents were a conspicuous feature of two of the tumor cells lines but were rarely observed in whole cell recordings of normal SC. The properties of Na+ currents recorded in both normal and tumor cells were not significantly different. Treatment of normal SC with a membrane-permeant analog of cyclic AMP (cAMP) resulted in functional expression of the TEA-only-sensitive K currents typical of tumor cells. These results establish the abnormal ion channel profile of neurofibromatosis type 1 (NF1)-tumor cells and suggest (Guo et al.: Science 276:795-798, 1997) that regulation of ionic currents by second messengers may involve the NF1 gene.

4-Aminopyridine↗

PubMed1988

Schwann cell surfaces but not extracellular matrix organized by Schwann cells support neurite outgrowth from embryonic rat retina.

Despite evidence that glial cell surfaces and components of the extracellular matrix (ECM) support neurite outgrowth in many culture systems, the relative contributions of these factors have rarely been compared directly. Specifically, it remains to be determined which components of peripheral nerve support growth of central nerve fibers. We have directly compared neurite outgrowth from embryonic day 15 rat retinal explants placed onto beds of (1) Schwann cells without ECM, (2) Schwann cells expressing ECM (including a basal lamina), (3) cell-free ECM prepared from neuron-Schwann cell cultures, (4) nonglial cells (fibroblasts), and (5) 2 isolated ECM components, laminin and type I collagen. From the first day in culture, retinal explants extended neurites when placed on Schwann cells without ECM. Outgrowth on Schwann cells expressing ECM was also extensive, but not obviously different form that on Schwann cells alone. Ultrastructural study revealed that 95% of retinal neurites in ECM-containing cultures contacted other neurites and Schwann cell surfaces exclusively. On cell-free ECM prepared from neuron-Schwann cell cultures, neurite extension was poor to nonexistent. No neurite outgrowth occurred on fibroblasts. Retinal explants also failed to extend neurites onto purified laminin and ammoniated type I collagen substrata; however, growth was rapid and extensive on air-dried type I collagen. In cultures containing islands of air-dried type I collagen on a laminin-coated coverslip, retinal explants attached and extended neurites on collagen, but these neurites did not extend off the island onto the laminin substratum. We conclude from these experiments that neurite extension from embryonic rat retina is supported by a factor found on the surface of Schwann cells and that neither organized nor isolated ECM components provide this neurite promotion. These findings are discussed in relation to possible species differences in growth requirements for retinal ganglion cell neurites and to the specificity of response of different CNS neurites to ECM substrata.

Animals↗

PubMed2004

The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation.

Schwann cells are a regenerative cell type. Following nerve injury, a differentiated myelinating Schwann cell can dedifferentiate and regain the potential to proliferate. These cells then redifferentiate during the repair process. This behaviour is important for successful axonal repair, but the signalling pathways mediating the switch between the two differentiation states remain unclear. Sustained activation of the Ras/Raf/ERK cascade in primary cells results in a cell cycle arrest and has been implicated in the differentiation of certain cell types, in many cases acting to promote differentiation. We therefore investigated its effects on the differentiation state of Schwann cells. Surprisingly, we found that Ras/Raf/ERK signalling drives the dedifferentiation of Schwann cells even in the presence of normal axonal signalling. Furthermore, nerve wounding in vivo results in sustained ERK signalling in associated Schwann cells. Elevated Ras signalling is thought to be important in the development of Schwann cell-derived tumours in neurofibromatosis type 1 patients. Our results suggest that the effects of Ras signalling on the differentiation state of Schwann cells may be important in the pathogenesis of these tumours.

Animals↗

PubMed2004

Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination.

Schwann cells are the myelinating glia of the peripheral nervous system, and their development is regulated by various growth factors, such as neuregulin, platelet-derived growth factor (PDGF), and insulin-like growth factor-I (IGF-I). However, the mechanism of intracellular signaling pathways following these ligand stimuli in Schwann cell differentiation remains elusive. Here, we demonstrate that in cultured Schwann cells, neuregulin and PDGF suppressed the expression of myelin-associated protein markers, whereas IGF-I promoted it. Although these ligands activated common downstream signaling pathways [i.e., extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)-Akt pathways], the profiles of activation varied among ligands. To elucidate the function of these pathways and the mechanisms underlying Schwann cell differentiation, we used adenoviral vectors to selectively activate or inactivate these pathways. We found that the selective activation of Erk pathways suppressed Schwann cell differentiation, whereas that of PI3K pathways promoted it. Furthermore, lithium chloride, a modulator of glycogen synthase kinase-3beta (GSK-3beta) promoted Schwann cell differentiation, suggesting the involvement of GSK-3beta as a downstream molecule of PI3K-Akt pathways. Selective activation of PI3K pathways in Schwann cells by gene transfer also demonstrated increased myelination in in vitro Schwann cell-DRG neuron cocultures and in vivo allogenic nerve graft experiments. We conclude that signals mediated by PI3K-Akt are crucial for initiation of myelination and that the effects of growth factors are primarily dependent on the balance between Erk and PI3K-Akt activation. Our results also propose the possibility of augmenting Schwann cell functions by modulating intracellular signals in light of future cell therapies.

Animals↗

PubMed1994

Antibody of patients with Guillain-Barré syndrome mediates complement-dependent cytolysis of rat Schwann cells: susceptibility to cytolysis reflects Schwann cell phenotype.

We previously observed that demyelination of dissociated dorsal root ganglion cultures by acute phase serum of some Guillain Barré syndrome (GBS) patients was associated with cytolysis of rat Schwann cells (SC) not committed to myelination. In this study, to determine if SC cytolysis was antibody (Ab) and complement-dependent and if SC at various stages of differentiation were uniformly susceptible, sciatic nerve SC from 1-2-day-old (SC/2d) or 6-day-old (SC/6d) Sprague Dawley rats were sensitized with IgM from GBS patients or normal controls and incubated at 37 degrees C for 60 min with 25% guinea pig serum complement. Cytolysis was detected by vital dye exclusion. IgM Ab of 11 GBS patients induced complement-mediated cytolysis of 10.7-64.1% SC/2d (38.3 +/- 18.8; mean +/- SD) which was significantly higher than cytolysis of SC/6d (8.5-32%) or that by normal controls (15.0 +/- 15.2 SC/2d; 8.3 +/- 3.3 SC/6d mean +/- SD, n = 11). Culture of SC/6d increased their cytolysis by IgM plus complement to the levels similar to that of SC/2d. FACS analysis suggested that the greater sensitivity of SC/2d to cytolysis did not reflect greater antibody binding since 2.6-fold less GBS IgM was required to initiate SC/2d lysis compared to SC/6d. This suggested that the less differentiated SC were more susceptible to complement-mediated cytolysis.

Animals↗

PubMed1999

Multiple connexin expression in peripheral nerve, Schwann cells, and Schwannoma cells.

Myelinating Schwann cells express the gap junction protein, connexin (Cx)32, which is present at the nodes of Ranvier and Schmidt-Lantermann incisures (Bergoffen et al. [1993] Science (Wash. ) 262:2039-2042). Following peripheral nerve injury, other members of the connexin gene family are also expressed (Chandross et al. [1996a] Mol. Cell. Neurosci. 7:501-518). This study surveys the connexin(s) expressed by rat sciatic nerve, cultured Schwann cells, and a mouse Schwannoma (TR6 Bc1) cell line. Reverse transcriptase-polymerase chain reaction (RT-PCR) amplification revealed a constitutive expression of mRNA encoding Cx32 and 43 but not Cx26, 37, 40, 45, and 46 in sciatic nerve. Mitogenic stimulation of cultured Schwann cells expressing Cx32 also resulted in the appearance of Cx43 mRNA. Schwannoma cells expressed exclusively Cx43 mRNA. These results were confirmed by Northern blot analysis. Functional gap junctions in cultured Schwann and Schwannoma cells were shown by analysis of the intercellular transfer of Lucifer yellow, although the coupling between primary Schwann cells was weak or undetectable. Treatment of primary Schwann cells with mitogens resulted in extensive dye coupling. An immunohistochemical study of adult sciatic nerve sections demonstrated Cx32 immunoreactivity at the nodes of Ranvier and in Schwann cell bodies. Lower intensity staining of Cx43 along the myelin sheath and Schwann cell bodies was also observed. Indirect immunofluorescent studies of Schwann cells treated with mitogens showed characteristic punctate cell surface staining of Cx43; Cx32 staining was detected mainly intracellularly. These results lead to the conclusion that in addition to the expression of Cx32 by normal adult sciatic nerve, low amounts of Cx43 protein are also present. The implications of the expression of two connexins by Schwann cells in Charcot-Marie-Tooth X-linked disease, a demyelinating peripheral neuropathy, are discussed.

Animals↗

PubMedDate not supplied

[The development, phenotypic characteristics and communications of Schwann cells].

The Schwann cell is one of the major cell types in vertebrate peripheral nervous system. The Schwann cell precursors are derived from the neural crest and migrate along the growing axons towards their ultimate localization. Recently obtained data regarding expression of different molecules (S100 protein, myelin proteins, low-affinity nerve growth factor receptor, GAP-43, adhesion molecules) and particularly transcription factors SCIP and Krox-20 allowed to precisely characterize lineage for myelinating and non myelinating Schwann cells and their phenotypes. The special attention to communication between neurones and Schwann cells is paid. The advance in study of the biology of Schwann cell is of great practical importance for understanding the molecular basis of neuropathies and posttraumatic peripheral nerve regeneration. Schwann cells are also considered as intriguously perspective candidates for transplantation into CNS to stimulate regeneration of axons in brain and spinal cord.

Animals↗

PubMed1985

Voltage-dependent sodium and potassium channels in mammalian cultured Schwann cells.

Cultured Schwann cells from sciatic nerves of newborn rabbits and rats have been examined with patch-clamp techniques. In rabbit cells, single sodium and potassium channels have been detected with single channel conductances of 20 pS and 19 pS, respectively. Single sodium channels have a reversal potential within 15 mV of ENa, are blocked by tetrodotoxin, and have rapid and voltage-independent inactivation kinetics. Single potassium channels show current reversal close to EK and are blocked by 4-aminopyridine. From these results, and from comparisons of single-channel and whole-cell data, we show that these Schwann cells contain voltage-dependent sodium and potassium channels that are similar in most respects to the corresponding channels in mammalian axonal membranes. Cultured rat Schwann cells also have sodium channels, but at a density about 1/10th that of rabbit cells, a result in agreement with saxitoxin binding experiments on axon-free sectioned nerves. Saxitoxin binding to cultured cells suggests that there are up to 25,000 sodium channels in a single rabbit Schwann cell. We speculate that in vivo Schwann cells in myelinated axons might act as a local source for sodium channels at the nodal axolemma.

Animals↗

PubMed1999

Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system.

Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells, and it promotes angiogenesis in vivo. Here we report that VEGF(165) has neurotrophic actions on cultured adult mouse superior cervical ganglia (SCG) and dorsal root ganglia (DRG), measured as axonal outgrowth. Maximal effect was observed at 10-50 ng/ml for SCG and 100 ng/ml for DRG. VEGF-induced axonal outgrowth was inhibited by the mitogen-activated protein kinase kinase inhibitor PD 98059 but not by the protein kinase inhibitor K252a. VEGF also increased survival of both neurons and satellite cells and the number of proliferating Schwann cells. Immunocytochemistry and immunoblotting revealed that VEGF was expressed in virtually all nerve cells in the SCG but only in a population of small-diameter (<35 micrometers) neurons representing approximately 30% of the neurons in DRG. Immunostaining showed that the VEGF receptor fetal liver kinase receptor (flk-1) was found on nerve cell bodies in DRG and to a lesser extent on neurons in SCG. Growth cones of regenerating axons from both types of ganglia exhibited flk-1 immunoreactivity, as did Schwann cells. We conclude that VEGF has both neurotrophic and mitogenic activity on cells in the peripheral nervous system.

Animals↗

PubMed2000

Long-term effect of vital labelling on mixed Schwann cell cultures.

Schwann cell transplantation following neuronal injury could encourage regeneration of spinal cord as well as improving peripheral nerve gap repair. In order to gain a better understanding of the role of transplanted Schwann cells in vivo, it is essential to be able to follow their behaviour after transplantation. Our aim was to evaluate the suitability of two vital fluorescent labels on the proliferation rate and phenotypic stability of Schwann cells, in either pure culture or mixed co-culture. Primary cultures of Schwann cells were obtained from Dark Agouti and Lewis neonatal rats and labelled with H33342 and PKH26, respectively. In mixed cultures, a 50: 50 mixture of Dark Agouti and Lewis Schwann cells was present. Labelled cultured cells were examined at 1, 2 and 4 weeks for viability and phenotypic marker expression of S100, GFAP, p75, MHC I, MHC II and compared with corresponding unlabelled cells. The results showed that although there was no deleterious interaction in the mixed cultures, the viability was reduced by the labelling after 2 weeks. Labelled cells could be distinguished up to 4 weeks, but there was leakage of H33342 label after 2 weeks. Labelled Schwann cells showed reduced expression of phenotypic markers, especially p75 when labelled with H33342. In conclusion, H33342 and PKH26 can be used as fluorescent markers of Schwann cells for short-term studies, for a maximum of 2 weeks, but different markers may be needed for longer experiments.

Animals↗

PubMed2006

In vitro and in vivo differentiation of boundary cap neural crest stem cells into mature Schwann cells.

Boundary cap cells can generate neurons as well as peripheral glia during embryonic development (Maro, G.S., Vermeren, M., Voiculescu, O., Melton, L., Cohen, J., Charnay, P., Topilko, P., 2004. Neural crest boundary cap cells constitute a source of neuronal and glial cells of the PNS. Nat Neurosci. 7 (9), 930-938), and, recently, the boundary cap was shown to contain multipotent stem cells (Hjerling-Leffler, J., Marmigère, F., Heglind, M., Cederberg, A., Koltzenburg, M., Enerbäck, S., Ernfors, P., 2005. The boundary cap, a source of neural crest stem cells generating multiple sensory neuron subtypes. Development. 132 (11), 2623-2632). The ability of stem cells to generate mature functional glial phenotypes has not been addressed. In this study, we have explored the competence of boundary neural crest stem cells (bNCSCs) to differentiate into mature functional Schwann cells (SCs) in vitro and in vivo. bNCSCs failed to differentiate into SCs in vitro when cultured in a defined media and in vivo when grafted into adult rat sciatic nerves. However, in the presence of neuregulins, during long-term cultures, the majority of bNCSCs differentiated into SCs. After analysis of the in vivo expression of Sox2, Sox10, S100, GFAP, fibronectin and Krox20 in the glial lineages, we used these markers to characterize differentiation of the bNCSCs. Gliogenesis of bNCSCs proceeded similar to that in vivo by sequentially adopting a SC precursor and immature Schwann cell before maturing into myelinating and non-myelinating SCs. In co-culture with explanted dorsal root ganglia (DRG) as well as in vivo in transplants to the axotomized sciatic nerve, these bNCSC-derived SCs myelinated axons as shown by ensheathing of neuronal processes and expression of myelin basic proteins (MBP). These results show that, under appropriate conditions, bNCSCs can generate mature SCs that are functional and can myelinate axons in regenerating nerves.

Animals↗

PubMed2006

Distinct roles for RB loss on cell cycle control, cisplatin response, and immortalization in Schwann cells.

Schwann cells play a critical role in peripheral nerve function. Regulated proliferation of Schwann cells is an important facet of the response to nerve injury; however, aberrant proliferation can give rise to Schwann cell tumors such as malignant peripheral nerve sheath tumors (MPNST). These tumors exhibit a range of genetic lesions that include loss of the retinoblastoma tumor suppressor (RB) pathway. RB plays a critical role in the regulation of cellular proliferation and its loss is a common event in human cancers. Here, the specific action of RB loss on Schwann cell proliferation and response to therapeutic intervention was explored. In primary mouse Schwann cells, conditional RB loss led to increased levels of critical cell cycle regulatory gene products, yet provided only a modest influence on proliferation. However, RB-deficient Schwann cells efficiently bypassed the cell cycle inhibitory response to the chemotherapeutic agent cisplatin, which is used in the treatment of MPNST and other glial tumors. Surprisingly, RB loss did not facilitate Schwann cell immortalization; and RB-deficient cells actually were less prone to immortalization than cells containing RB. Furthermore, RB-deficient cells that ultimately re-entered the cell cycle had lost both Schwann cell morphology and markers. Since, RB loss is likely a late event in Schwann cell tumor progression, the action of acute RB loss in immortalized Schwann cells was investigated. In this context, loss of RB had a profound effect on expression of target genes and the response to cisplatin. Thus, the loss of RB in both primary and immortal Schwann cells disrupted the response to anti-mitogenic signals and has implications for therapeutic intervention.

Animals↗

PubMed2001

Interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta inhibit cyclic AMP-induced Schwann cell differentiation.

Schwann cells differentiate in vivo in response to contact with axons, and cAMP simulates some of these aspects of differentiation in vitro, particularly morphologic changes and expression of certain phenotypic molecules. Unfractionated inflammatory cytokines inhibit cAMP-induced Schwann cell expression of galactolipids (Gal). We sought to identify which cytokines were responsible for this inhibition and to determine whether other phenotypic indicators of Schwann cell differentiation were also affected. Neonatal rat Schwann cells were incubated in vitro with 1 mM 8 Bromo cAMP (8 Br cAMP) with or without the addition of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), or transforming growth factor-beta (TGF-beta). Cells were then examined for morphologic changes and for expression of surface Gal and low-affinity nerve growth factor receptor (NGFRp75), employing indirect immunofluorescence. 8 Br cAMP induced Schwann cell upregulation of Gal, downregulation of NGFRp75, and the cells became enlarged and somewhat amorphous and irregular in appearance. Cells treated with IFN-gamma or TNF-alpha alone were more bipolar and more evenly distributed on coverslips than were control cells, whereas TGF-beta alone induced elongated cells often in a swirling pattern. None of the cytokines alone induced upregulation of Gal or downregulation of NGFRp75. TNF-alpha, IFN-gamma, and TGF-beta inhibited the 8 Br cAMP-induced morphologic changes, as well as the upregulation of Gal and downregulation of NGFRp75. The other cytokines had no effects on Gal or NGFRp75 expression. Thus, these three cytokines, which are present in inflammatory lesions in the peripheral nervous system, are capable of inhibiting Schwann cell differentiation.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1995

Calcitonin gene-related peptide promotes Schwann cell proliferation.

Schwann cells in culture divide in response to defined mitogens such as PDGF and glial growth factor (GGF), but proliferation is greatly enhanced if agents such as forskolin, which increases Schwann cell intracellular cAMP, are added at the same time as PDGF or GGF (Davis, J. B., and P. Stroobant. 1990. J. Cell Biol. 110:1353-1360). The effect of forskolin is probably due to an increase in numbers of PDGF receptors (Weinmaster, G., and G. Lemke. 1990. EMBO (Eur. Mol. Biol. Organ.) J. 9:915-920. Neuropeptides and beta-adrenergic agonists have been reported to have no effect on potentiating the mitogenic response of either PDGF or GGF. We show that the neuropeptide calcitonin gene-related peptide (CGRP) increases Schwann cell cAMP levels, but the cells rapidly desensitize. We therefore stimulated the cells in pulsatile fashion to partly overcome the effects of desensitization and show that CGRP can synergize with PDGF to stimulate Schwann cell proliferation, and that CGRP is as effective as forskolin in the pulsatile regime. CGRP is a good substrate for the neutral endopeptidase 24.11. Schwann cells in vivo have this protease on their surface, so the action of CGRP could be terminated by this enzyme and desensitization prevented. We therefore suggest that CGRP may play an important role in stimulating Schwann cell proliferation by regulating the response of mitogenic factors such as PDGF.

Animals↗

PubMed1996

Immunology of the Schwann cell.

The Schwann cell or its myelin membrane appears to be the focus of autoimmune attack in several peripheral neuropathies. Potential Schwann cell antigens have therefore been extensively studied. Of the known Schwann cell proteins, MBP, P2, MAG, PLP, PO, PMP-22 and Connexin 32, gene defects of the latter three have recently been shown to be responsible for some forms of hereditary sensory and motor neuropathies. The L2/HNK-1 epitope, common to MAG, Po and PMP-22, is the target of autoantibody damage in neuropathies associated with certain IgM paraproteinaemias. P2, the inciting antigen in rat EAN, has no demonstrated role in human neuropathies. The same appears true for the glycolipid galactocerebroside, a neuritogen in rabbits. Gangliosides are currently under intense study, but the antigen for the common inflammatory neuropathies remains undefined. Evidence for the potential role of Schwann cells in immune modulation is provided; Schwann cells produced MHC molecules, the adhesion molecules I-CAM1, L1, L2-HNK-1, Ng-CAM, N-cadherisn, the cytokines IL-1, IL-6 and TNF-alpha and the inflammatory prostanoids, PGE-2 AND TxA2.

Animals↗