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

Einheber, Steven; Hannocks, Melanie-Jane; Metz, Christine N.; Rifkin, Daniel B.; Salzer, James L.

doi:10.1083/jcb.129.2.443

Cited by 148 publications

(95 citation statements)

References 65 publications

(71 reference statements)

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“…The different outcome of the co-culture experiments on the one hand and the direct knock-down of NT3 in vivo on myelination is paralleled in experiments in which the effects of transforming growth factor (TGF)b were examined in co-culture or in vivo. TGFb inhibits myelination in co-cultures (Einheber et al, 1995), whereas knockout of TGFb signaling specifically in Schwann cells has no effects on myelination but reduces Schwann cell proliferation and death in developing nerves (D'Antonio et al, 2006). This emphasizes the importance of timing and the context in which a particular molecule exerts its effects.…”

Section: Neurotrophin 3 (Nt3)mentioning

confidence: 99%

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Jessen

Mirsky

2008

Glia

445

400

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Dedifferentiation of myelinating Schwann cells is a key feature of nerve injury and demyelinating neuropathies. We review recent evidence that this dedifferentiation depends on activation of specific intracellular signaling molecules that drive the dedifferentiation program. In particular, we discuss the idea that Schwann cells contain negative transcriptional regulators of myelination that functionally complement positive regulators such as Krox-20, and that myelination is therefore determined by a balance between two opposing transcriptional programs. Negative transcriptional regulators should be expressed prior to myelination, downregulated as myelination starts but reactivated as Schwann cells dedifferentiate following injury. The clearest evidence for a factor that works in this way relates to c-Jun, while other factors may include Notch, Sox-2, Pax-3, Id2, Krox-24, and Egr-3. The role of cell-cell signals such as neuregulin-1 and cytoplasmic signaling pathways such as the extracellular-related kinase (ERK)1/2 pathway in promoting dedifferentiation of myelinating cells is also discussed. We also review evidence that neurotrophin 3 (NT3), purinergic signaling, and nitric oxide synthase are involved in suppressing myelination. The realization that myelination is subject to negative as well as positive controls contributes significantly to the understanding of Schwann cell plasticity. Negative regulators are likely to have a major role during injury, because they promote the transformation of damaged nerves to an environment that fosters neuronal survival and axonal regrowth. In neuropathies, however, activation of these pathways is likely to be harmful because they may be key contributors to demyelination, a situation which would open new routes for clinical intervention. V V C 2008 Wiley-Liss, Inc.

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Section: Neurotrophin 3 (Nt3)mentioning

confidence: 99%

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Jessen

Mirsky

2008

Glia

445

400

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“…DRG neuron coculture with Schwann cells was performed using the modified method of Einheber et al (1995). Briefly, DRGs were taken from E15 rats, dissociated with 0.25% trypsin, and seeded on 12 mm dishes coated with collagen type I at 200,000 cells per well.…”

Section: Methodsmentioning

confidence: 99%

Opposing Extracellular Signal-Regulated Kinase and Akt Pathways Control Schwann Cell Myelination

Ogata¹,

Iijima²,

Hoshikawa³

et al. 2004

J. Neurosci.

232

211

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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.

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“…Primary rat Schwann cells, dorsal root ganglion (DRG) neurons, and myelinating Schwann cell-DRG coculture were established as described previously (Einheber et al, 1995). Schwann cell cultures were kept in serum-containing media (D media) consisting of DMEM (BioWhittaker, Walkersville, MD), 10% FBS (Hyclone Laboratories, Logan, UT), and 2 mM L-glutamine (Invitrogen, Gaithersburg, MD) until used.…”

Section: Methodsmentioning

confidence: 99%

“…Control and treated myelinating cocultures were processed as described previously (Einheber et al, 1995) or by a "stamp" method. For the latter, cultures grown on collagen-coated glass coverslips were rinsed in PBS and fixed overnight at 4°C in 2% glutaraldehyde diluted in 0.1 M phosphate buffer, pH 7.0 (0.1 M PB).…”

Section: Methodsmentioning

confidence: 99%

Rho Kinase Regulates Schwann Cell Myelination and Formation of Associated Axonal Domains

Melendez‐Vasquez

Einheber²,

Salzer³

2004

J. Neurosci.

105

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The myelin sheath forms by the spiral wrapping of a glial membrane around an axon. The mechanisms involved are poorly understood but are likely to involve coordinated changes in the glial cell cytoskeleton. Because of its key role as a regulator of the cytoskeleton, we investigated the role of Rho kinase (ROCK), a major downstream effector of Rho, in Schwann cell morphology, differentiation, and myelination. Pharmacologic inhibition of ROCK activity results in loss of microvilli and stress fibers in Schwann cell cultures and strikingly aberrant myelination in Schwann cell-neuron cocultures; there was no effect on Schwann cell proliferation or differentiation. Treated Schwann cells branch aberrantly and form multiple, small, independent myelin segments along the length of axons, each with associated nodes and paranodes. This organization partially resembles myelin formed by oligodendrocytes rather than the single long myelin sheath characteristic of Schwann cells. ROCK regulates myosin light chain phosphorylation, which is robustly, but transiently, activated at the onset of myelination. These results support a key role of Rho through its effector ROCK in coordinating the movement of the glial membrane around the axon at the onset of myelination via regulation of myosin phosphorylation and actomyosin assembly. They also indicate that the molecular machinery that promotes the wrapping of the glial membrane sheath around the axon is distributed along the entire length of the internode.

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

Cited by 148 publications

References 65 publications

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Opposing Extracellular Signal-Regulated Kinase and Akt Pathways Control Schwann Cell Myelination

Rho Kinase Regulates Schwann Cell Myelination and Formation of Associated Axonal Domains

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