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PubMed1994

Role for the stem cell factor/KIT complex in Schwann cell neoplasia and mast cell proliferation associated with neurofibromatosis.

Schwann cells are the primary cell type in the disfiguring lesions associated with neurofibromatosis type 1 (NF-1). These lesions also contain abnormally high numbers of mast cells, a cell type which develops in response to stem cell factor. We report here that neonatal and adult rat and human Schwann cells, as well as a transfected rat Schwann cell line and a human Schwannoma line derived from an NF-1 patient, all produced stem cell factor mRNA and protein. In coculture experiments, surface expression of stem cell factor by neonatal rat Schwann cells was profoundly downregulated by contact with dorsal root ganglion neurites. The receptor for stem cell factor, KIT, was not expressed in normal Schwann cells but was expressed in the human Schwannoma line, suggesting that aberrant KIT expression may form an autocrine loop in certain Schwann cell neoplasias.

Animals↗
PubMed1996

Cell death in the Schwann cell lineage and its regulation by neuregulin.

The development of Schwann cells, the myelin-forming glial cells of the vertebrate peripheral nervous system, involves a neonatal phase of proliferation in which cells migrate along and segregate newly formed axons. Withdrawal from the cell cycle, around postnatal days 2-4 in rodents, initiates terminal differentiation to the myelinating state. During this time, Schwann cell number is subject to stringent regulation such that within the first postnatal week, axons and myelinating Schwann cells attain the one-to-one relationship characteristic of the mature nerve. The mechanisms that underly this developmental control remain largely undefined. In this report, we examine the role of apoptosis in the determination of postnatal Schwann cell number. We find that Schwann cells isolated from postnatal day 3 rat sciatic nerve undergo apoptosis in vitro upon serum withdrawal and that Schwann cell death can be prevented by beta forms of neuregulin (NRG-beta) but not by fibroblast growth factor 2 or platelet-derived growth factors AA and BB. This NRG-beta-mediated Schwann cell survival is apparently transduced through an ErbB2/ErbB3 receptor heterodimer. We also provide evidence that postnatal Schwann cells undergo developmentally regulated apoptosis in vivo. Together with other recent findings, these results suggest that Schwann cell apoptosis may play an important role in peripheral nerve development and that Schwann cell survival may be regulated by access to axonally derived NRG.

Animals↗
PubMed1990

Expression of recombinant myelin-associated glycoprotein in primary Schwann cells promotes the initial investment of axons by myelinating Schwann cells.

Myelin-associated glycoprotein (MAG) is an integral membrane protein expressed by myelinating glial cells that occurs in two developmentally regulated forms with different carboxyterminal cytoplasmic domains (L-MAG and S-MAG). To investigate the role of MAG in myelination a recombinant retrovirus was used to introduce a MAG cDNA (L-MAG form) into primary Schwann cells in vitro. Stably infected populations of cells were obtained that constitutively expressed MAG at the cell surface without the normal requirement for neuronal contact to induce expression. Constitutive expression of L-MAG did not affect myelination. In long term co-culture with purified sensory neurons, the higher level of MAG expression on infected Schwann cells was reduced to control levels on cells that formed myelin. On the other hand, unlike normal Schwann cells, infected Schwann cells associated with nonmyelinated axons or undergoing Wallerian degeneration expressed high levels of MAG. This suggests that a posttranscriptional mechanism modulates MAG expression during myelination. Immunostaining myelinating cultures with an antibody specific to L-MAG showed that L-MAG was normally transiently expressed at the earliest stages of myelination. In short term co-culture with sensory neurons, infected Schwann cells expressing only L-MAG segregated and ensheathed larger axons after 4 d in culture provided that an exogenous basal lamina was supplied. Similar activity was rarely displayed by control Schwann cells correlating with the low level of MAG induction after 4 d. These data strongly suggest that L-MAG promotes the initial investment by Schwann cells of axons destined to be myelinated.

Animals↗
PubMed2001

Schwann cell type V collagen inhibits axonal outgrowth and promotes Schwann cell migration via distinct adhesive activities of the collagen and noncollagen domains.

Previously, we reported the cloning of alpha4 type V collagen, a novel member of the collagen type V gene family that is expressed by Schwann cells in developing peripheral nerves (Chernousov et al., 2000). The present study was performed to investigate the effects of this collagen on the adhesion and migration of premyelinating Schwann cells and neurite outgrowth from embryonic dorsal root ganglion neurons. Purified alpha4(V)-containing collagen isolated from Schwann cell conditioned medium (collagen type V(SC)) promoted migration of Schwann cells but inhibited outgrowth of axons from rat embryo dorsal root ganglia. Collagen type V(SC) blocked axonal outgrowth in the presence of otherwise active substrates such as collagen type IV, indicative of active inhibition. The noncollagen N-terminal domain of alpha4(V) promoted Schwann cell adhesion, spreading, and migration. These processes were inhibited by soluble heparin but not by function-blocking antibodies against alpha1- and alpha2-integrins. The collagen domain of pepsin-digested collagen type V was poorly adhesive for Schwann cells. The type V collagen domain but not the alpha4(V) N-terminal domain blocked neurite outgrowth from dorsal root ganglion neurons. In cocultures of dorsal root ganglion neurons and Schwann cells, collagen type V(SC) promoted axon fasciculation and association of axons with Schwann cells. These results suggest that in embryonic peripheral nerves, collagen type V(SC) plays a dual role in regulating cell migration. This represents a heretofore unrecognized function of peripheral nerve collagen fibrils in regulating patterns of peripheral nerve growth during development.

Animals↗
PubMed1984

Cell lineage analysis of Schwann cells in the PNS determined by shiverer-normal mouse chimeras.

The myelin of the peripheral nervous system from the shiverer mutant mice is characterized by the absence of myelin basic protein, while the other myelin protein components are present at normal levels. Myelin lamella formation is normal in the shiverer mutant. Therefore, by using antiserum against myelin basic protein, we can distinguish the shiverer from the wild-type control myelin immunohistochemically. To study the cell lineage of Schwann cells, chimeras produced by the aggregation of eight-cell embryos from wild-type mice and shiverer mice have been used. Using myelin basic protein as a marker, it was observed that Schwann cells in the sciatic nerve existed as patches of cells with like-genotype. The patches occurred in a linear array along the axons with some intermingling of Schwann cells. Complete randomization by intermingling of Schwann cells was not observed and clones of Schwann cells may persist as contiguous groups throughout peripheral nerve development.

Animals↗
PubMed1996

Axon-Schwann cell interactions regulate the expression of c-jun in Schwann cells.

The transcription factor c-jun is selectively expressed by non-myelinating Schwann cells in normal peripheral nerve, and be "denervated," previously myelinatng Schwann cells, after axotomy. When axons regenerate into the distal nerve-stump, the expression of c-jun declines as Schwann cells remyelinate axons. Treating cultured Schwann cells with forskolin, a drug that mimics many of the effects of axon-Schwann cell interactions, decreases the expression of myelin-specific genes. Overexpressing c-jun in cultured Schwann cells, however, does not decrease the expression of a myelin basic protein promoter-reporter construct, indicating that c-jun expression may not directly regulate myelin-specific gene expression. These data suggest that c-jun is invloved in regulating the phenotype of non-myelinating and denervated Schwann cells.

Animals↗
PubMed2005

Identification by microarray analysis of aspartate aminotransferase and glutamine synthetase as glucocorticoid target genes in a mouse Schwann cell line.

Schwann cells have been identified as targets for glucocorticoids. Besides genes implicated in the myelination process, the target genes of glucocorticoids have not been identified in these cells. For that purpose, we performed microarray analysis on MSC80 (mouse Schwann cells) treated with a synthetic glucocorticoid, dexamethasone. These cells express a functional glucocorticoid receptor (GR), but none of the other steroid receptors. This allowed us to identify genes specifically regulated by GR in the absence of the mineralocorticoid receptor. Among the 5000 genes analyzed, 12 were at least two-fold upregulated and 91 genes were at least two-fold down-regulated upon treatment with dexamethasone. Because of their potential role in Schwann cell homeostasis, we selected, for further analysis, the upregulated genes encoding glutamine synthetase (GS) and cytosolic aspartate aminotransferase (cAspAT). These genes play a crucial role in the glutamate cycle which was shown to be vital in neuron-astrocyte cross-talk in the central nervous system. Their activation was confirmed by semi-quantitative and real-time PCR. A detailed analysis of cAspAT promoter activity revealed that the mechanism of regulation by GR in Schwann cells differs from that in hepatoma cells, suggesting a cell-specific regulation. The transactivation potency of the two Glucocorticoid Responsive Units (GRU) present in the cAspAT promoter seems to be dependent on the levels of the GR in MSC80 cells. Furthermore, we show that an increase in GR levels under certain circumstances could considerably potentiate the effects of glucocorticoids on the cAspAT promoter via synergistic activation of both GRU, To the opposite, an enhancement in GR levels did not further potentiate Dex-activation of the GS promoter, showing a differential mechanism of action of GR in the context of both promoters.

Animals↗
PubMed1988

Expression of Schwann cell characteristics in pigmented nevus. Immunohistochemical study using monoclonal antibody to Schwann cell associated antigen.

A monoclonal antibody to the Schwann cell associated antigen (AHMY1) and a monoclonal antibody to neurofilament proteins (NFP) (AHNF1) each were produced. Using AHMY1, AHNF1, and anti-S-100 antibody, 90 pigmented nevi were examined immunohistochemically to clarify the relationship between nevus cells and Schwann cells. All nevus cells had S-100 protein, but did not have neurofilament proteins. The nevic corpuscle and Type C nevus cell were positively stained with AHMY1 indicating the presence of the Schwann cell associated antigen, while Type A and B nevus cells were entirely negative. This suggests that the nevic corpuscle and Type C nevus cell are closely related to the Schwann cell and differ from Type A and B nevus cells in their development.

Antibodies, Monoclonal↗
PubMed1994

Organization of microtubules in myelinating Schwann cells.

Myelinating Schwann cells polarize their surface membrane into several ultrastructurally and biochemically distinct domains that constitute the myelin internode. Formation of these membrane domains depends on contact with appropriate axons and requires microtubule-based transport systems for site-specific targeting of membrane components. Because little is known about microtubules in myelinating Schwann cells, this study used confocal microscopy and the microtubule hook-labelling method to characterize microtubule distribution, the location of microtubule nucleation sites, and the polarity and composition of Schwann cell microtubules. In myelinating Schwann cells, microtubules were abundant within the Golgi-rich perinuclear cytoplasm; they were not attached to the centrosome. Three-fourths of the microtubules in the cytoplasmic channels located along the outer perimeter of the myelin internode had their (+) ends oriented away from the perinuclear region, whereas the remaining 25% had the opposite polarity. Depolymerization/repolymerization experiments detected microtubule nucleating sites in perinuclear cytoplasm but not along the myelin internode. Taken together, these results indicate that microtubule-mediated transport of myelin components along the internode could utilize both (+)- and (-)-end motors. Specialized microtubule tracks that target myelin proteins to specific sites were not identified on the basis of tubulin polarity or posttranslational modifications.

Aging↗
PubMed1989

Axonal signals regulate expression of glia maturation factor-beta in Schwann cells: an immunohistochemical study of injured sciatic nerves and cultured Schwann cells.

Glia maturation factor-beta (GMF-beta) is a 17 kDa protein purified and sequenced from bovine brains. Using the monoclonal antibody G2-09 directed against GMF-beta, we previously demonstrated endogenous GMF-beta in astroblasts, Schwann cells, and their tumors in culture. In the present study, we have used indirect immunofluorescence microscopy with G2-09 to examine the effects of transection, crush, and regeneration of sciatic nerve on the expression of GMF-beta in Schwann cells in situ and to study the time course of GMF-beta induction in Schwann cells in vitro. For comparison, a parallel study was carried out with monoclonal antibodies directed against nerve growth factor (NGF) receptor. We found that (1) neither GMF-beta nor NGF receptor was detectable in intact sciatic nerves, (2) all Schwann cells of the distal segment of the transected nerve expressed GMF-beta as early as 3 d after axotomy that persisted up to 3 weeks, (3) axonal regeneration repressed the Schwann cell expression of GMF-beta, (4) isolated Schwann cells derived from rat sciatic and adult human sural nerves developed intracellular GMF-beta in culture following an initial lag period, and (5) the induction of Schwann cell NGF receptor coincided temporally with that of GMF-beta in the transected nerve and in culture. These results show that the expression of GMF-beta in Schwann cells, as is the case with the NGF receptor, is induced by the loss of the normal axon-Schwann cell contact. We propose that the induction of GMF-beta, as well as NGF receptor, in Schwann cells after nerve injury plays a role in axonal regeneration.

Animals↗
PubMed2006

Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage.

We have investigated the phenotypic and bioassay characteristics of bone marrow mesenchymal stromal cells (MSCs) differentiated along a Schwann cell lineage using glial growth factor. Expression of the Schwann cell markers S100, P75, and GFAP was determined by immunocytochemical staining and Western blotting. The levels of the stem cell markers Stro-1 and alkaline phosphatase and the neural progenitor marker nestin were also examined throughout the differentiation process. The phenotypic properties of cells differentiated at different passages were also compared. In addition to a phenotypic characterization, the functional ability of differentiated MSCs has been investigated employing a co-culture bioassay with dissociated primary sensory neurons. Following differentiation, MSCs underwent morphological changes similar to those of cultured Schwann cells and stained positively for all three Schwann cell markers. Quantitative Western blot analysis showed that the levels of S100 and P75 protein were significantly elevated upon differentiation. Differentiated MSCs were also found to enhance neurite outgrowth in co-culture with sensory neurons to a level equivalent or superior to that produced by Schwann cells. These findings support the assertion that MSCs can be differentiated into cells that are Schwann cell-like in terms of both phenotype and function.

Alkaline Phosphatase↗
PubMed1987

Growth of axons into developing muscles of the chick forelimb is preceded by cells that stain with Schwann cell antibodies.

A study has been made of the development of limb and muscle nerves in relation to the first appearance of Schwann cells in the flexor digitorum profundus (fdp) and flexor carpi ulnaris (fcu) muscles of the avian forelimb. Schwann cells were identified by immunofluorescent techniques with antibodies to the glycoprotein HNK-1. Myotubes and nerves were identified by using antibodies to myosin and to neurofilament, respectively. At stage 24/25 the brachialis longus inferior (Bli n) and superior (Bls n) nerve trunks within proximal regions of the forelimb were surrounded by Schwann cells. These cells extended in a column for a distance of approximately 100 microns beyond the growing ends of nerves. At stage 26 both interosseus nerve (in n) and the medial-ulnar nerve (m-u n) had formed from the Bli n; each of these branches was surrounded by Schwann cells, which again extended approximately 100 microns beyond the growing ends of the nerves. By stage 26/27 the fdp and fcu muscles were clearly delineated by groups of myotubes. No nerves were detected within these groups; however, Schwann cells were observed between the myotubes. At stage 27 axons had left the in n and m-u n and grown into the fdp and fcu muscles, respectively. These axons were surrounded by Schwann cells. The present observations show that Schwann cells are located ahead of the main limb and muscle nerves as they grow into the fdp and fcu muscles of the limb. It is possible that these Schwann cells play a role in guiding nerves to their correct muscles in the developing chick forelimb.

Animals↗
PubMed1987

Rat Schwann cell remyelination of demyelinated cat CNS axons: evidence that injection of cell suspensions of CNS tissue results in Schwann cell remyelination.

Injection of a suspension of embryonic rat central nervous system (CNS) cells into an area of persistent demyelination, produced in the cat spinal cord by injecting ethidium bromide into an area previously exposed to 40 Grays of x-irradiation, results, initially, in Schwann cell remyelination of the demyelinated axons. However, the Schwann cells are subsequently rejected; a response which confirms that the remyelinating cells are of rat origin.

Animals↗
PubMed1995

Schwann cells and fetal tectal tissue cografted to the midbrain of newborn rats: fate of Schwann cells and their influence on host retinal innervation of grafts.

Schwann cells transplanted into the adult central nervous system (CNS) can exert powerful growth-promoting effects on damaged axons. An important issue is whether central axons induced to regrow by Schwann cells retain the capacity to recognize and selectively innervate their appropriate target cells. To examine how Schwann cells may influence the specificity of neuron-neuron interactions in CNS neuropil, we cultured neonatal rat Schwann cells and mixed them with dissociated fetal tectal cells. In some instances, Schwann cells were prelabeled with Hoechst dye 33342. Schwann cells comprised between 2.5 and 15% of the combined cell population. After reaggregation, cografts were injected onto the midbrain of newborn rats. One to 6 months later, grafts were examined for the presence of Schwann cells and the pattern and density of host retinal innervation of the cografts was assessed. Immunohistochemical studies showed that areas of the transplants containing large numbers of surviving Hoechst-labeled Schwann cells were strongly immunoreactive for the low-affinity nerve growth factor receptor (p75), S-100, GFAP, and laminin. Very little peripheral (Po positive) myelin was seen. As in pure fetal tectal grafts, host retinal axons were sometimes observed to innervate superficial, localized areas in the cografts known to be homologous to the retinorecipient layers of the superior colliculus. Unlike pure tectal grafts, however, optic axons were not confined to these regions and fibers were often dispersed within the cograft neuropil. Dense growth was seen in association with Hoechst-labeled Schwann cells and, in some cases, optic axons were observed to grow toward Schwann cells and away from nearby target areas. These observations suggest that, under certain circumstances, Schwann cells can stimulate retinal axons to grow into inappropriate (nontarget) regions in the CNS, presumably by producing growth promoting factors which mask or compete with signals released from the target neurons themselves.

Animals↗
PubMed2000

Cell cycle control of Schwann cell proliferation: role of cyclin-dependent kinase-2.

Schwann cell proliferation is regulated by multiple growth factors and axonal signals. However, the molecules that control growth arrest of Schwann cells are not well defined. Here we describe regulation of the cyclin-dependent kinase-2 (CDK2) protein, an enzyme that is necessary for the transition from G1 to S phase. Levels of CDK2 protein were elevated in proliferating Schwann cells cultured in serum and forskolin. However, when cells were grown with either serum-free media or at high densities, CDK2 levels declined to low levels. The decrease in CDK2 levels was associated with growth arrest of Schwann cells. The modulation of CDK2 appears to be regulated at the transcriptional level, because CDK2 mRNA levels and its promoter activity both decline during cell cycle arrest. Furthermore, analysis of the CDK2 promoter suggests that Sp1 DNA binding sites are essential for maximal activation in Schwann cells. Together, these data suggest that CDK2 may represent a significant target of developmental signals that regulate Schwann cell proliferation and that this regulation is mediated, in part, through regulation of Sp1 transcriptional activity.

Animals↗
PubMedDate not supplied

A cell surface protein of astrocytes, Ran-2, distinguishes non-myelin-forming Schwann cells from myelin-forming Schwann cells.

Defining the molecular phenotype of adult glial cells in the peripheral nervous system in situ forms a good basis for subsequent studies on the development of these cells, and for determining the role of neurons in the attainment and maintenance of the mature glial phenotype. We report here the characterization of the glial surface antigen, Ran-2, and describe its distribution in the peripheral and central nervous system of adult rats. Immunoprecipitation of the antigen from cultured astrocytes with monoclonal Ran-2, antibodies, showed that Ran-2 is a protein with an apparent molecular weight of 140,000 daltons. In immunofluorescence studies of teased nerve preparations, Ran-2 was found on the surface of non-myelin-forming Schwann cells in all nerves surveyed, i.e. the sciatic, dorsal and ventral roots, cervical sympathetic trunk and the brachial plexus. In contrast, it was not detected immunohistochemically on myelin-forming Schwann cells. The antigen was also absent, or present at very low levels, on the satellite cells of dorsal root sensory ganglia, although, as we reported previously, it was present on the glial cells of the enteric nervous system. The Ran-2 antigen was also associated with perineurial cells. In short-term cell cultures of the sciatic nerve and cervical sympathetic trunk from 19-day-old rats, Ran-2 could be localized on the surface of individual viable Schwann cells. In the central nervous system, the antigen was present on astrocytes in sections of the optic nerve.

Animals↗
PubMed2006

Schwann cell preparation from single mouse embryos: analyses of neurofibromin function in Schwann cells.

The study of peripheral nerve function in development and disease can be facilitated by the availability of cultured cells that faithfully mimic in vivo Schwann cell growth, maturation, and differentiation. We have developed a method to establish purified mouse Schwann cell culture from a single embryo at embryonic day 12.5 (E12.5) to define the abnormalities in Schwann cells caused by loss of the neurofibromatosis type 1 (Nf1) tumor suppressor protein, the RAS-GAP neurofibromin. Our method generates 2-3 x 10(6) cells/embryo highly purified (>99.5%) mouse Schwann cells in less than 2 weeks from a single E12.5 mouse embryo. Manipulation of cell medium allows purification of a Schwann-like cell population, termed Nf1-/-TXF, that resembles a tumorigenic cell in that it grows dissociated from axons and grows rapidly, yet retains expression of Schwann cell markers. We describe the preparation and characterization of both cell types.

Animals↗