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S S Scherer

Publications and source records attributed to S S Scherer.

At least 55 records · Page 3Linked to original sources
PubMed1997

The biology and pathobiology of Schwann cells.

The most common forms of inherited demyelinating neuropathy in humans are caused by mutations in the genes encoding protein zero, peripheral myelin protein 22 kDa, and connexin32, all of which are expressed by myelinating Schwann cells and are components of the myelin sheath. The phenotype of myelinating Schwann cells depends on the maintenance of axon-Schwann cell interactions, because axonal degeneration also leads to the breakdown of the myelin sheath and dedifferentiation of the previously myelinating cells into 'denervated' Schwann cells, which are essential for axonal regeneration. Several transcription factors have been shown to play critical roles in regulating the phenotype of Schwann cells, including SCIP/tst-1/Oct-6 and Krox-20, both of which are required for the normal development of the myelinating phenotype.

Animals↗
PubMed1997

Autosomal dominant transmission of Dejerine-Sottas disease (HMSN III).

Hereditary motor-sensory neuropathy type III (HMSN III) (Dejerine-Sottas disease) is a severe demyelinating neuropathy that is traditionally considered autosomal recessive. We report a father and daughter diagnosed with HMSN III by clinical, electrophysiologic, and pathologic criteria, thus showing that it may be transmitted in an autosomal dominant fashion in selected families.

Adolescent↗
PubMed1997

Heterozygous P0 knockout mice develop a peripheral neuropathy that resembles chronic inflammatory demyelinating polyneuropathy (CIDP).

Demyelinating peripheral neuropathies are clinically divided into inherited and acquired types. Inherited demyelinating neuropathies are caused by mutations in genes expressed by myelinating Schwann cells, whereas acquired ones, including chronic inflammatory demyelinating polyneuropathy (CIDP), are probably caused by autoimmune mechanisms. We find that heterozygous P0 knockout (P0+/-) mice develop a neuropathy that resembles CIDP. By one year of age, P0+/- mice develop severe, asymmetric slowing of motor nerves, with temporal dispersion or conduction block, which are features of acquired demyelinating neuropathies including CIDP. Moreover, morphological analysis of affected nerves reveals severe and selective demyelination of motor fibers, focal regions of demyelination, and inflammatory cells. These data suggest that immune-mediated mechanisms may contribute to the pathogenesis of the neuropathy in P0+/- mice.

Action Potentials↗
PubMed1996

Expression of the neurofibromatosis 2 tumor suppressor gene product, merlin, in Schwann cells.

The neurofibromatosis 2 (NF2) tumor suppressor gene encodes a protein with sequence similarity to a family of molecules linking cell membrane proteins to the actin cytoskeleton. Individuals affected with NF2 develop schwannomas at an increased frequency. In this paper, we report that merlin is expressed in Schwann cells, where it is localized in vitro to the cell membrane by immunohistochemistry and subcellular fractionation. Exogenous expression of merlin fragments confirms this subcellular distribution and suggests that both the N-terminal and C-terminal portions of the molecule are required for this localization. In addition, merlin is expressed in rat sciatic nerve Schwann cells at paranodal membranes, where it colocalizes with RhoA. Lastly, expression of the NF2 gene increases during postnatal rat sciatic nerve development, consistent with its role as a negative growth regulator for Schwann cells. These results collectively suggest that merlin may function at the cell surface to modulate cell growth in Schwann cells and to link cell membrane proteins to the cytoskeleton.

Actin Cytoskeleton↗
PubMed1996

Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins.

Programmed cell death during development resulting from the lack of appropriate survival factors has been demonstrated in both neurons and oligodendrocytes and occurs mostly in the form of apoptosis. We now demonstrate that Schwann cells in the rat sciatic nerve undergo apoptosis during early postnatal development and that the amount of apoptosis is markedly increased by axotomy. The apoptotic Schwann cells express the low-affinity nerve growth factor receptor but not myelin-related proteins, indicating that they are in the premyelinating state. Apoptosis resulting from normal development or from axotomy can be inhibited markedly by exogenous neuregulin. Consistent with this, the neuregulin receptor components erbB2 and erbB3 are expressed and phosphorylated in developing sciatic nerve. These data suggest that Schwann cell number in developing peripheral nerve is regulated by apoptosis through competition for axonally derived neuregulin.

Aging↗
PubMed1996

Molecular specializations at nodes and paranodes in peripheral nerve.

In the peripheral nervous system, nodes of Ranvier are formed by interactions between myelinating Schwann cells and axons. Nodes have an intricate ultrastructure, and their molecular architecture is similarly complex. A growing list of molecules have been found that are selectively localized to different parts of the nodes. Neural cell adhesion molecule (N-CAM), L1/Ng-CAM, and tenascin/cytotactin are enriched in the nodal basal lamina; hyaluronic acid, versican/hyaluronectin, N-CAM, L1/Ng-CAM, tenascin/cytotactin, and the ganglioside GM1 are enriched in the nodal gap; myelin-associated glycorprotein, oligodendrocyte-myelin glycoprotein, connexin32, E-cadherin, actin, the gangliosides GQ1b and GD1b, the potassium channel KV1.5, and alkaline phosphatase are enriched in the paranodal region of the Schwann cell; voltage-dependent sodium channels and the cytoskeletal proteins spectrin and ankyrin are enriched in the nodal axolemma. Many of these molecules are probably essential for the proper functioning and stability of nodes.

Animals↗
PubMed1996

Tst-1/Oct-6/SCIP regulates a unique step in peripheral myelination and is required for normal respiration.

The terminal differentiation of myelinating glia involves complex interactions that culminate in the formation of myelin. The POU domain transcription factor Tst-1/Oct-6/SCIP is expressed transiently during myelination, and we report here that it has a critical role in this developmental process. Deletion of the Tst-1/Oct-6/SCIP gene produces a severe defect in peripheral myelination by arresting Schwann cell maturation before axonal wrapping. Unexpectedly, the activation of major myelin-specific genes appears to be unaffected by the Tst-1/Oct-6/SCIP mutation, demonstrating that multiple, independently regulated events are required for terminal differentiation of Schwann cells. In addition, aberrant differentiation and migration of specific neurons in Tst-1/Oct-6/SCIP mutant homozygotes is associated with a fatal breathing defect, providing a model for investigating the regulation of pulmonary homeostasis.

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↗
PubMed1996

The transcription factors SCIP and Krox-20 mark distinct stages and cell fates in Schwann cell differentiation.

We have studied the transcription factors SCIP and Krox-20 in differentiating Schwann cells-during normal development, in experimentally induced degenerating and regenerating peripheral nerves, and in cell culture-and have compared the expression of these regulators to a battery of genes that mark distinct stages in Schwann cell differentiation. In the myelinating Schwann cell lineage, we find that SCIP is initially induced by contact with axons and first appears near the last round of cell division in immature cells. This expression is transient--it is maximal in "promyelinating" cells and is then extinguished as Schwann cells overtly differentiate and myelinate axons. In contrast, Krox-20 appears in cells 24-36 h after they become SCIP+ and continues to be expressed in mature myelinating cells. These differences in regulation are seen in normal development, in regenerating nerves following nerve crush, and in cultured Schwann cells stimulated to adopt a myelination phenotype by elevation of intracellular cyclic AMP. Importantly, transient SCIP expression is also observed in the nonmyelinating Schwann cell lineage, but Krox-20 expression is not. Together with the myelination phenotypes exhibited by SCIP and Krox-20 mutant mice, these results suggest that SCIP preferentially acts during the predifferentiated phases of Schwann cell development, while in contrast, Krox-20 is associated with the later commitment to myelination and may therefore function as a direct transactivator of myelination genes.

Animals↗
PubMed1996

Chronic inflammatory demyelinating polyneuropathy associated with malignant melanoma.

We report three patients who developed chronic inflammatory demyelinating polyneuropathy (CIDP) in association with malignant melanoma. In two cases, melanoma was discovered during the initial evaluation for neuropathy. Two patients also had vitiligo, an antibody-mediated disorder that may complicate melanoma. Melanoma cells and Schwann cells are both of neuroectodermal cell origin, with shared surface antigens. Shared immunoreactivity may account for the association between melanoma and CIDP, as with vitiligo.

Adult↗
PubMed1995

An adenoviral vector can transfer lacZ expression into Schwann cells in culture and in sciatic nerve.

Although a number of genetic defects in the P0, peripheral myelin protein-22, and connexin-32 genes recently were shown to cause the demyelinating forms of Charcot-Marie-Tooth disease, there is yet no effective treatment for these patients. Recent studies showed that replication defective adenoviral vectors can efficiently introduce genes into muscle, brain, lung, and other tissues, suggesting that this vector system may be useful for the treatment of a number of genetic diseases. In this work, we demonstrated that a replication deficient adenovirus expressing the Escherichia coli beta-galactosidase gene (AdCMVLacZ) can introduce genes into Schwann cells, in culture as well as in sciatic nerve. Schwann cells cultured at a multiplicity of infection of 250:1 did not demonstrate cytopathic effects. Following injection of AdCMVLacZ into sciatic nerve of rats, lacZ-expressing, myelinating Schwann cells could be detected for at least 45 days. These data suggest that in the future, these vectors may be useful both in perturbing Schwann cell gene expression and in designing therapies for the treatment of Charcot-Marie-Tooth disease.

Adenoviruses, Human↗
PubMed1995

Regulation of neurofibromin expression in rat sciatic nerve and cultured Schwann cells.

Loss of function mutations at the NF1 locus may act intrinsically in Schwann cells to cause the formation of benign Schwann cell tumors (neurofibromas) in patients with type 1 neurofibromatosis. To identify contexts in Schwann cells in which such mutations may play an important role, we measured the levels of NF1 mRNA and neurofibromin in rat sciatic nerve during development, after axotomy, and in cultured rat Schwann cells. NF1 mRNA was present in developing sciatic nerve throughout the period of active Schwann cell proliferation and myelination. After nerve transection, no alteration in NF1 message level was detected, but neurofibromin levels increased, as assessed by immunohistochemistry and Western blotting, suggesting that, in vivo, neurofibromin expression in Schwann cells is post-transcriptionally induced during Wallerian degeneration. Cultured rat Schwann cells constitutively expressed NF1 mRNA and neurofibromin. Schwann cell proliferation induced by exposure to serum and forskolin was not associated with changes in NF1 mRNA or neurofibromin expression, whereas Schwann cell proliferation induced by extracts of embryonic brain membranes was associated with increased NF1 message and neurofibromin expression. Thus, Schwann cells, both in vivo and in vitro, express NF1 mRNA constitutively; the expression of NF1 mRNA and neurofibromin is modulated by only some mitogenic stimuli in Schwann cells.

Animals↗
PubMed1995

Hepatitis C infection, cryoglobulinemia, and vasculitic neuropathy. Treatment with interferon alfa: case report and literature review.

A patient with mononeuropathy multiplex, hepatitis C viral infection, and mixed cryoglobulinemia had axonal degeneration by EMG and vasculitis of the epineurial vessels on sural nerve biopsy. There was no evidence of viral particles in the nerve by immunofluorescence. Treatment with interferon alfa improved the patient's symptoms and cleared the hepatitis C viral RNA and cryoglobulins from the serum.

Adult↗
PubMed1995

Periaxin expression in myelinating Schwann cells: modulation by axon-glial interactions and polarized localization during development.

Periaxin is a newly described protein that is expressed exclusively by myelinating Schwann cells. In developing nerves, periaxin is first detected as Schwann cells ensheathe axons, prior to the appearance of the proteins that characterize the myelin sheath. Periaxin is initially concentrated in the adaxonal membrane (apposing the axon) but, during development, as myelin sheaths mature, periaxin becomes predominately localized at the abaxonal Schwann cell membrane (apposing the basal lamina). In permanently axotomized adult nerves, periaxin is lost from the abaxonal and adaxonal membranes, becomes associated with degenerating myelin sheaths and is phagocytosed by macrophages. In crushed nerves, in which axons regenerate and are remyelinated, periaxin is first detected in the adoxonal membrane as Schwann cells ensheathe regenerating axons, but again prior to the appearance of other myelin proteins. Periaxin mRNA and protein levels change in parallel with those of other myelin-related genes after permanent axotomy and crush. These data demonstrate that periaxin is expressed by myelinating Schwann cells in a dynamic, developmentally regulated manner. The shift in localization of periaxin in the Schwann cell after completion of the spiralization phase of myelination suggests that periaxin participates in membrane-protein interactions that are required to stabilize the mature myelin sheath.

Animals↗
PubMed1995

Connexin32 is a myelin-related protein in the PNS and CNS.

We have examined the expression of a gap junction protein, connexin32 (Cx32), in Schwann cells and oligodendrocytes. In peripheral nerve, Cx32 is found in the paranodal myelin loops and Schmidt-Lanterman incisures of myelinating Schwann cells, and the levels of Cx32 protein and mRNA change in parallel with those of other myelin-related genes during development, Wallerian degeneration, and axonal regeneration. In the central nervous system, Cx32 is found in oligodendrocytes and their processes, but not in compact myelin, and the levels of Cx32 protein and mRNA increase during development in parallel with those of the other myelin genes. Thus, Cx32 is expressed as part of the myelinating phenotype of both Schwann cells and oligodendrocytes, indicating that this gap junction protein plays in important role in the biology of myelin-forming cells.

Animals↗
PubMed1994

Expression of multiple neuregulin transcripts in postnatal rat brains.

The distribution of neuregulin transcripts in rat brains was studied by both RNA blotting and in situ hybridization. Our data demonstrate that multiple neuregulin transcripts are expressed in neurons of the basal forebrain, the hippocampus, the diencephalon, the cerebellum, the brainstem, and the spinal cord. Developmental changes in the distribution of neuregulin transcripts were observed only in the cerebellum and the hippocampus. The intense neuregulin hybridization signals in the brainstem motor and sensory nuclei and the spinal motor neurons are suggestive of a functional involvement of neuregulins in motor and sensory systems. The expression of neuregulins in other parts of the brain also indicates that these factors are involved in a variety of central nervous system functions.

Animals↗