Krox-20 controls SCIP expression, cell cycle exit and susceptibility to apoptosis in developing myelinating Schwann cells

Development ◽  
1999 ◽  
Vol 126 (7) ◽  
pp. 1397-1406 ◽  
Author(s):  
T.S. Zorick ◽  
D.E. Syroid ◽  
A. Brown ◽  
T. Gridley ◽  
G. Lemke
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Cell Phenotype ◽  
Mouse Mutants ◽  
Morphological Criteria ◽  
Genes Encoding ◽  
Initial Appearance ◽  
Time Courses ◽  
Myelinating Schwann Cell ◽  
Cellular Phenotypes

The transcription factors Krox-20 and SCIP each play important roles in the differentiation of Schwann cells. However, the genes encoding these two proteins exhibit distinct time courses of expression and yield distinct cellular phenotypes upon mutation. SCIP is expressed prior to the initial appearance of Krox-20, and is transient in both the myelinating and non-myelinating Schwann cell lineages; while in contrast, Krox-20 appears approximately 24 hours after SCIP and then only within the myelinating lineage, where its expression is stably maintained into adulthood. Similarly, differentiation of SCIP−/− Schwann cells appears to transiently stall at the promyelinating stage that precedes myelination, whereas Krox-20(−/−) cells are, by morphological criteria, arrested at this stage. These observations led us to examine SCIP regulation and Schwann cell phenotype in Krox-20 mouse mutants. We find that in Krox-20(−/−) Schwann cells, SCIP expression is converted from transient to sustained. We further observe that both Schwann cell proliferation and apoptosis, which are normal features of SCIP+ cells, are also markedly increased late in postnatal development in Krox-20 mutants relative to wild type, and that the levels of cell division and apoptosis are balanced to yield a stable number of Schwann cells within peripheral nerves. These data demonstrate that the loss of Krox-20 in myelinating Schwann cells arrests differentiation at the promyelinating stage, as assessed by SCIP expression, mitotic activity and susceptibility to apoptosis.

Expression of Schwann cell markers by mammalian neural crest cells in vitro

Development ◽  
1989 ◽  
Vol 105 (2) ◽  
pp. 251-262 ◽  
Author(s):  
L.C. Smith-Thomas ◽  
J.W. Fawcett
Keyword(s):  
Monoclonal Antibody ◽  
Schwann Cell ◽  
Embryonic Development ◽  
Neural Crest ◽  
Schwann Cells ◽  
Neural Crest Cell ◽  
Neural Crest Cells ◽  
Similar Proportion ◽  
Cell Phenotype ◽  
Cell Markers

During embryonic development, neural crest cells differentiate into a wide variety of cell types including Schwann cells of the peripheral nervous system. In order to establish when neural crest cells first start to express a Schwann cell phenotype immunocytochemical techniques were used to examine rat premigratory neural crest cell cultures for the presence of Schwann cell markers. Cultures were fixed for immunocytochemistry after culture periods ranging from 1 to 24 days. Neural crest cells were identified by their morphology and any neural tube cells remaining in the cultures were identified by their epithelial morphology and immunocytochemically. As early as 1 to 2 days in culture, approximately one third of the neural crest cells stained with m217c, a monoclonal antibody that appears to recognize the same antigen as rat neural antigen-1 (RAN-1). A similar proportion of cells were immunoreactive in cultures stained with 192-IgG, a monoclonal antibody that recognizes the rat nerve growth factor receptor. The number of immunoreactive cells increased with time in culture. After 16 days in culture, nests of cells, many of which had a bipolar morphology, were present in the area previously occupied by neural crest cells. The cells in the nests were often associated with neurons and were immunoreactive for m217c, 192-IgG and antibody to S-100 protein and laminin, indicating that the cells were Schwann cells. At all culture periods examined, neural crest cells did not express glial fibrillary acidic protein. These results demonstrate that cultured premigratory neural crest cells express early Schwann cell markers and that some of these cells differentiate into Schwann cells. These observations suggest that some neural crest cells in vivo may be committed to forming Schwann cells and will do so provided that they then proceed to encounter the correct environmental cues during embryonic development.

scholarly journals Transforming growth factor-beta 1 regulates axon/Schwann cell interactions.

1995 ◽  
Vol 129 (2) ◽  
pp. 443-458 ◽  
Author(s):  
S Einheber ◽  
M J Hannocks ◽  
C N Metz ◽  
D B Rifkin ◽  
J L Salzer
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cell Interactions ◽  
Receptor Expression ◽  
Cell Phenotype ◽  
Beta Activity ◽  
Tgf Beta

We have investigated the potential regulatory role of TGF-beta in the interactions of neurons and Schwann cells using an in vitro myelinating system. Purified populations of neurons and Schwann cells, grown alone or in coculture, secrete readily detectable levels of the three mammalian isoforms of TGF-beta; in each case, virtually all of the TGF-beta activity detected is latent. Expression of TGF-beta 1, a major isoform produced by Schwann cells, is specifically and significantly downregulated as a result of axon/Schwann cell interactions. Treatment of Schwann cells or Schwann cell/neuron cocultures with TGF-beta 1, in turn, has dramatic effects on proliferation and differentiation. In the case of purified Schwann cells, treatment with TGF-beta 1 increases their proliferation, and it promotes a pre- or nonmyelinating Schwann cell phenotype characterized by increased NCAM expression, decreased NGF receptor expression, inhibition of the forskolin-mediated induction of the myelin protein P0, and induction of the Schwann cell transcription factor suppressed cAMP-inducible POU protein. Addition of TGF-beta 1 to the cocultures inhibits many of the effects of the axon on Schwann cells, antagonizing the proliferation induced by contact with neurons, and, strikingly, blocking myelination. Ultrastructural analysis of the treated cultures confirmed the complete inhibition of myelination and revealed only rudimentary ensheathment of axons. Associated defects of the Schwann cell basal lamina and reduced expression of laminin were also detected. These effects of TGF-beta 1 on Schwann cell differentiation are likely to be direct effects on the Schwann cells themselves which express high levels of TGF-beta 1 receptors when cocultured with neurons. The regulated expression of TGF-beta 1 and its effects on Schwann cells suggest that it may be an important autocrine and paracrine mediator of neuron/Schwann cell interactions. During development, TGF-beta 1 could serve as an inhibitor of Schwann cell proliferation and myelination, whereas after peripheral nerve injury, it may promote the transition of Schwann cells to a proliferating, nonmyelinating phenotype, and thereby enhance the regenerative response.

scholarly journals c-Jun is a negative regulator of myelination

2008 ◽  
Vol 181 (4) ◽  
pp. 625-637 ◽  
Author(s):  
David B. Parkinson ◽  
Ambily Bhaskaran ◽  
Peter Arthur-Farraj ◽  
Luke A. Noon ◽  
Ashwin Woodhoo ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Schwann Cell ◽  
Cell Biology ◽  
Gene Activation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Negative Regulator ◽  
Cell Phenotype ◽  
Myelinating Schwann Cell

Schwann cell myelination depends on Krox-20/Egr2 and other promyelin transcription factors that are activated by axonal signals and control the generation of myelin-forming cells. Myelin-forming cells remain remarkably plastic and can revert to the immature phenotype, a process which is seen in injured nerves and demyelinating neuropathies. We report that c-Jun is an important regulator of this plasticity. At physiological levels, c-Jun inhibits myelin gene activation by Krox-20 or cyclic adenosine monophosphate. c-Jun also drives myelinating cells back to the immature state in transected nerves in vivo. Enforced c-Jun expression inhibits myelination in cocultures. Furthermore, c-Jun and Krox-20 show a cross-antagonistic functional relationship. c-Jun therefore negatively regulates the myelinating Schwann cell phenotype, representing a signal that functionally stands in opposition to the promyelin transcription factors. Negative regulation of myelination is likely to have significant implications for three areas of Schwann cell biology: the molecular analysis of plasticity, demyelinating pathologies, and the response of peripheral nerves to injury.

scholarly journals Dynamic Environmental Physical Cues Activate Mechanosensitive Responses in the Repair Schwann Cell Phenotype

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 425
Author(s):  
Michele Fornaro ◽  
Dominic Marcus ◽  
Jacob Rattin ◽  
Joanna Goral
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Cell Phenotype ◽  
Environmental Cues ◽  
Key Factors ◽  
Functional Changes ◽  
Physical Conditions ◽  
Physical Cues ◽  
External Stimuli ◽  
Regenerating Nerve

Schwann cells plastically change in response to nerve injury to become a newly reconfigured repair phenotype. This cell is equipped to sense and interact with the evolving and unusual physical conditions characterizing the injured nerve environment and activate intracellular adaptive reprogramming as a consequence of external stimuli. Summarizing the literature contributions on this matter, this review is aimed at highlighting the importance of the environmental cues of the regenerating nerve as key factors to induce morphological and functional changes in the Schwann cell population. We identified four different microenvironments characterized by physical cues the Schwann cells sense via interposition of the extracellular matrix. We discussed how the physical cues of the microenvironment initiate changes in Schwann cell behavior, from wrapping the axon to becoming a multifunctional denervated repair cell and back to reestablishing contact with regenerated axons.

Beta 4 integrin expression in myelinating Schwann cells is polarized, developmentally regulated and axonally dependent

Development ◽  
1994 ◽  
Vol 120 (5) ◽  
pp. 1287-1301 ◽  
Author(s):  
M.L. Feltri ◽  
S.S. Scherer ◽  
R. Nemni ◽  
J. Kamholz ◽  
H. Vogelbacker ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Morphological Changes ◽  
Cell Phenotype ◽  
Integrin Subunit ◽  
Integrin Expression ◽  
Cultured Schwann Cells ◽  
Mediate Cell

In developing and regenerating peripheral nerve, Schwann cells interact with axons and extracellular matrix in order to ensheath and myelinate axons. Both of these interactions are likely to be mediated by adhesion molecules, including integrins, which mediate cell-cell and cell-extracellular matrix interactions. Recently, the beta 4 integrin subunit was reported to be expressed by Schwann cells in peripheral nerve. We have examined the expression of beta 4, beta 1 and their common heterodimeric partner, the alpha 6 integrin subunit, in developing and regenerating rat peripheral nerve. beta 4 and alpha 6 are enriched in peripheral nerve and they co-localize at the abaxonal surface of myelinating Schwann cells, opposite the Schwann cell basal lamina, which contains possible ligands of alpha 6 beta 4. In contrast, beta 4 and alpha 6 are expressed in a different pattern in non-myelinating Schwann cells. The level of beta 4, but not alpha 6 or beta 1 mRNAs, increases progressively in developing nerves, reaching a peak in adult nerves well after the peak of the myelin-specific mRNAs. After axotomy, the expression of beta 4 mRNA and protein, but not alpha 6 or beta 1 mRNAs, fall rapidly but subsequently are reinduced by regenerating axons. Similarly, in cultured Schwann cells, the expression of beta 4 mRNA, but not alpha 6 mRNA, is significantly modulated by forskolin, a drug that elevates cAMP and mimics some of the effects of axonal contact. beta 4 integrin expression in Schwann cells, therefore, is regulated by Schwann cell-axon interactions, which are known to be critical in determining the Schwann cell phenotype. Furthermore, the polarized expression of alpha 6 beta 4 to the abaxonal surface of myelinating Schwann cells suggests that alpha 6 beta 4 may mediate in part the morphological changes required of Schwann cells in the process of myelination in the peripheral nervous system.

scholarly journals Distribution and role in regeneration of N-CAM in the basal laminae of muscle and Schwann cells.

1988 ◽  
Vol 107 (2) ◽  
pp. 707-719 ◽  
Author(s):  
F Rieger ◽  
M Nicolet ◽  
M Pinçon-Raymond ◽  
M Murawsky ◽  
G Levi ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Nerve Regeneration ◽  
Schwann Cells ◽  
Basal Lamina ◽  
Close Association ◽  
Axon Terminals ◽  
Muscle Extract ◽  
Cell Processes ◽  
Myelinating Schwann Cell

The neural cell adhesion molecule (N-CAM) is a membrane glycoprotein involved in neuron-neuron and neuron-muscle adhesion. It can be synthesized in various forms by both nerve and muscle and it becomes concentrated at the motor endplate. Biochemical analysis of a frog muscle extract enriched in basal lamina revealed the presence of a polydisperse, polysialylated form of N-CAM with an average Mr of approximately 160,000 as determined by SDS-PAGE, which was converted to a form of 125,000 Mr by treatment with neuraminidase. To define further the role of N-CAM in neuromuscular junction organization, we studied the distribution of N-CAM in an in vivo preparation of frog basal lamina sheaths obtained by inducing the degeneration of both nerve and muscle fibers. Immunoreactive material could be readily detected by anti-N-CAM antibodies in such basal lamina sheaths. Ultrastructural analysis using immunogold techniques revealed N-CAM in close association with the basal lamina sheaths, present in dense accumulation at places that presumably correspond to synaptic regions. N-CAM epitopes were also associated with collagen fibrils in the extracellular matrix. The ability of anti-N-CAM antibodies to perturb nerve regeneration and reinnervation of the remaining basal lamina sheaths was then examined. In control animals, myelinating Schwann cells wrapped around the regenerated axon and reinnervation occurred only at the old synaptic areas; new contacts between nerve and basal lamina had a terminal Schwann cell capping the nerve terminal. In the presence of anti-N-CAM antibodies, three major abnormalities were observed in the regeneration and reinnervation processes: (a) regenerated axons in nerve trunks that had grown back into the old Schwann cell basal lamina were rarely associated with myelinating Schwann cell processes, (b) ectopic synapses were often present, and (c) many of the axon terminals lacked a terminal Schwann cell capping the nerve-basal lamina contact area. These results suggest that N-CAM may play an important role not only in the determination of synaptic areas but also in Schwann cell-axon interactions during nerve regeneration.

scholarly journals Use of a new mouse schwannoma tumour model to monitor changes in peripheral nerve morphology in Merlin null Schwann cells

2021 ◽  
Vol 23 (Supplement_4) ◽  
pp. iv7-iv8
Author(s):  
Marie Srotyr ◽  
Liyam Laraba ◽  
Glenn M Harper ◽  
Charlotte Lespade ◽  
Evyn Woodhouse ◽  
...  
Keyword(s):  
Nervous System ◽  
Sciatic Nerve ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Erk Pathway ◽  
Tumour Formation ◽  
Immuno Histochemistry ◽  
Sciatic Nerves ◽  
Myelinating Schwann Cell

Abstract Aims Our lab is interested in signals that trigger schwannoma tumour formation and we have previously shown that peripheral nerve injury triggers tumour formation in nerves with Schwann cell-specific loss of the Merlin (NF2) tumour suppressor. The Ras/Raf/MAPK/ERK pathway activity in myelinating Schwann cells is involved in nerve regeneration, causing demyelination and recruitment of inflammatory cells in areas of nerve damage, as well as dedifferentiation of myelinating Schwann cells into a repair-competent state. We have used a mouse model expressing a tamoxifen-inducible Raf-Kinase estrogen receptor fusion protein (Raf-TR) in myelinating Schwann cells of the PNS in either a control wild-type Merlin or Merlin-null background. This allows us to determine the effects of an injury-like signal in Schwann cells and its role in generating schwannoma tumour development. We present here a detailed analysis of the proliferation of Schwann cells within the nerve and morphological changes in PNS structure following Raf-TR activation. Method The P0-promotor driving the Raf-TR transgene is active in myelinating Schwann cells but inactive in the non-myelinating population, allowing specific targeting of the myelinating Schwann cell population. In addition to the Raf-TR gene, the mice exhibit a separate P0-promotor controlled Cre floxed NF2 gene which undergoes Cre-mediated recombinase at embryonic day 13.5 causing NF2 knockout in all developing Schwann cells. Mice aged between 4-6 weeks received intraperitoneal injections of either 2mg Tamoxifen or oil vehicle for 5 consecutive days and were then studied at either 10 or 21 days post-first injection. The peripheral nervous system of the mice was studied with fluorescent immuno-histochemistry staining, semithin sections and transmission electron microscopy (TEM) on sciatic nerves and dorsal root ganglia (DRG). Results Activation of the Ras/Raf/MAPK/ERK pathway in NF2 null Schwann cells led to higher rates of proliferation within sciatic nerves at 10d post-tamoxifen injections. At both 10d and 21d Raf-TR+ NF2-null mice sciatic nerve fascicles were visibly larger with significantly more cell bodies present than controls, however at 21d the rate of proliferation had reduced. In the DRG, proliferation was higher in Raf-TR+ NF2-null mice compared to controls, with proliferation remaining high at 21 days. Quantitative imaging of peripheral nerve semi-thins analysed to date showed no significant difference in the number of myelin rings present in the fascicles between different genotypes. Additionally, dual immuno-histochemistry staining with Myelin Basic Protein and EdU, markers for myelin and proliferation respectively, appeared to show proliferation in the non-myelinating Schwann cell population. Results from staining with other cell markers will also be presented, as well as a detailed analysis of nerve structure using TEM. Conclusion While developmental myelination of Merlin-null Schwann cells appears largely normal, the reaction of Merlin-null Schwann cells in the nerve to an injury signal (activation of the Raf-TR) is remarkably different from those of control nerves. The high levels of proliferation in Merlin-null Schwann cells may be indicative of a higher tumorigenesis potential. While the proliferation of Merlin-null cells does reduce over time in the sciatic nerve, further experiments are now testing whether there may be ongoing tumour growth at other locations in the nervous system that are associated with NF2 tumours in human patients.

Axons regulate Schwann cell expression of the major myelin and NGF receptor genes

Development ◽  
1988 ◽  
Vol 102 (3) ◽  
pp. 499-504 ◽  
Author(s):  
G. Lemke ◽  
M. Chao
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Growth Factor Receptor ◽  
Myelin Proteins ◽  
Ngf Receptor ◽  
Genes Encoding ◽  
Messenger System ◽  
High Level ◽  
Cell Expression ◽  
Inductive Signal

The elaboration of myelin by Schwann cells is triggered by contact with appropriate peripheral axons. Among the most prominent features of this interaction is the activation and high-level expression of the genes encoding the major myelin proteins P0 and Myelin Basic Protein (MBP). Although the initial induction of these genes is thought to be dependent upon contact with axons, neither the inductive signal of the axon nor the receptor and associated second messenger system of the Schwann cell that transduces this signal has been identified. In this report, we demonstrate that expression of the P0 and MBP genes in rapidly myelinating Schwann cells is sharply reduced upon withdrawal of axons, but that this expression can be substantially restored by agents that raise the intracellular concentration of cyclic AMP. We further show that Schwann cell expression of a third gene, i.e. that encoding the Nerve Growth Factor receptor, is strongly activated by the withdrawal of axons, and that this activation is largely independent of cAMP.

Human Neurofibromas in Co-Culture with Mouse Neurons

1982 ◽  
Vol 40 ◽  
pp. 194-195
Author(s):  
R.L. Martuza ◽  
T. Liszczak ◽  
A. Okun ◽  
T-Y Wang
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Genetic Disorder ◽  
Cranial Nerves ◽  
Sympathetic Nerves ◽  
Acoustic Neuromas ◽  
Spinal Roots ◽  
Neural Crest Origin ◽  
Multiple Abnormalities ◽  
Other Neoplasms

Neurofibromatosis (NF) is an autosomal dominant genetic disorder with a prevalence of 1/3,000 births. The NF mutation causes multiple abnormalities of various cells of neural crest origin. Schwann cell tumors (neurofibromas, acoustic neuromas) are the most common feature of neurofibromatosis although meningiomas, gliomas, and other neoplasms may be seen. The schwann cell tumors commonly develop from the schwann cells associated with sensory or sympathetic nerves or their ganglia. Schwann cell tumors on ventral spinal roots or motor cranial nerves are much less common. Since the sensory neuron membrane is known to contain a mitogenic factor for schwann cells, we have postulated that neurofibromatosis may be due to an abnormal interaction between the nerve and the schwann cell and that this interaction may be hormonally modulated. To test this possibility a system has been developed in which an enriched schwannoma cell culture can be obtained and co-cultured with pure neurons.

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