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

Ogata, Toru; Iijima, Sumio; Hoshikawa, Shinya; Miura, Toshiki; Yamamoto, Shin Ichi; Oda, Hiromi; Nakamura, Kozo; Tanaka, Sakae

doi:10.1523/jneurosci.5520-03.2004

Cited by 234 publications

(250 citation statements)

References 45 publications

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“…It is known that SCs optimize the extracellular environment around peripheral nerves by demonstrating a considerable degree of plasticity (Jessen and Mirsky, 2005). In the uninjured state, mature SCs exist in a myelinating or non-myelinating state, characterized by a specific complement of transcription factors , signaling proteins (Ogata, et al, 2004), and extracellular markers (Taveggia, et al, 2005). Additionally, the expression of S100B, among other proteins, is strongly expressed in mature SCs, but is significantly downregulated in immature SCs and their precursors (Fornaro, et al, 2001, Jessen andMirsky, 2005).…”

Section: Discussionmentioning

confidence: 99%

Reinnervation of the tibialis anterior following sciatic nerve crush injury: A confocal microscopic study in transgenic mice

Magill

Tong

Kawamura

et al. 2007

Experimental Neurology

109

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Transgenic mice whose axons and Schwann cells express fluorescent chromophores enable new imaging techniques and augment concepts in developmental neurobiology. The utility of these tools in the study of traumatic nerve injury depends on employing nerve models that are amenable to microsurgical manipulation and gauging functional recovery. Motor recovery from sciatic nerve crush injury is studied here by evaluating motor endplates of the tibialis anterior muscle, which is innervated by the deep peroneal branch of the sciatic nerve. Following sciatic nerve crush, the deep surface of the tibialis anterior muscle is examined using whole mount confocal microscopy, and reinnervation is characterized by imaging fluorescent axons or Schwann cells (SCs). One week following sciatic crush injury, 100% of motor endplates are denervated with partial reinnervation at two weeks, hyperinnervation at three and four weeks, and restoration of a 1:1 axon to motor endplate relationship six weeks after injury. Walking track analysis reveals progressive recovery of sciatic nerve function by six weeks. SCs reveal reduced S100 expression within two weeks of denervation, correlating with regression to a more immature phenotype. Reinnervation of SCs restores S100 expression and a fully differentiated phenotype. Following denervation, there is altered morphology of circumscribed terminal Schwann cells demonstrating extensive process formation between adjacent motor endplates. The thin, uniformly innervated tibialis anterior muscle is well suited for studying motor reinnervation following sciatic nerve injury. Confocal microscopy may be performed coincident with other techniques of assessing nerve regeneration and functional recovery.

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Section: Discussionmentioning

confidence: 99%

Reinnervation of the tibialis anterior following sciatic nerve crush injury: A confocal microscopic study in transgenic mice

Magill

Tong

Kawamura

et al. 2007

Experimental Neurology

109

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“…In line with the possibility that neuregulin-1 is involved in Schwann cell dedifferentiation, there is evidence that ERK1/2 activation could play a role in demyelination (Agthong et al, 2006;Harrisingh et al, 2004;Ogata et al, 2004;Sheu et al, 2000). Phospho-ERK1/2 levels rise rapidly in the distal stump after transection and remain high until at least 16 days later, and activation is delayed at sites distal to the transection site compared with segments adjacent to the cut site itself (Harrisingh et al, 2004;Sheu et al, 2000).…”

Section: Erk1/2 and Neuregulin-1mentioning

confidence: 95%

“…There is increasing evidence that the cAMP pathway is indeed involved in normal myelination, and that the effects of cAMP may be mediated by NFjB and CREB (Yoon et al, 2008;Arthur-Farraj P, Mirsky R, Jessen KR, unpublished). Other signaling cascades that have been found to promote myelination include the phosphatidylinositol-3-kinase (PI3K)-Akt and p38 MAP kinase pathways (Fragoso et al, 2003;Haines et al, 2008;Maurel and Salzer, 2000;Ogata et al, 2004).…”

Section: Positive Regulators Of Myelinationmentioning

confidence: 99%

“…In vitro, selective activation of ERK1/2 signaling or alternatively overexpression of ras or raf, effector molecules upstream of ERK1/2, prevent Schwann cell differentiation in response to cAMP. Raf also induces downregulation of myelin proteins in cultures that have been induced to express myelin proteins in response to cAMP and demyelination in Schwann cell-DRG co-cultures (Harrisingh et al, 2004;Ogata et al, 2004). In the nerves of P 0 1/2 mice, examined as a model for Charcot-Marie Tooth neuropathy, ERK1/2 activation is seen in the nuclei of some myelinating Schwann cells at 6 months of age, and is directly linked to the increased production of the macrophage attractant cytokine MCP-1 in the nerves of these mice (Fischer et al, 2008).…”

Section: Erk1/2 and Neuregulin-1mentioning

confidence: 99%

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

Jessen

Mirsky

2008

Glia

451

409

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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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“…Prolonged exposure to estradiol stimulates proliferation and differentiation of OLs (Jung-Testas et al, 1992;Marin-Husstege et al, 2004;Zhang et al, 2004), and protects them from cell death because of hyperoxia or cytotoxic agents (Gerstner et al, 2007;Takao et al, 2004), but these effects may have been mediated through the nuclear receptor. To provide evidence for a role for a membrane ER in rapid signaling in OLs, we have investigated the effect of both 17a-and 17b-estradiol on short-term activation of several signaling pathways known to be involved in development of myelinating cells, involving MAPK, Akt, and GSK-3b (Cui et al, 2005;Khorchid et al, 1999;Ogata et al, 2004;Palacios et al, 2005). We show that truncated ERa and ERb are the main isoforms in the OL membrane and that the mER is involved in rapid signaling pathways, which are activated via both 17a-and 17b-estradiol.…”

Section: Introductionmentioning

confidence: 99%

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

Hirahara

Matsuda

Gao

et al. 2008

Glia

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There is general acceptance that the estrogen receptor can act as a transcription factor. However, estrogens can also bind to receptors that are located at the plasma membrane and stimulate rapid intracellular signaling processes. We recently showed that a membrane-associated estrogen receptor (mER) is present within myelin and at the oligodendrocyte (OL) plasma membrane. To understand the physiological function of mER in OLs, we investigated its cellular localization and involvement in rapid signaling in CG4 cells and OL primary cultures. An ERa was expressed along the lacy network of veins in the membrane sheets and in the perikaryon and nucleus in OLs. ERb was located in the nucleus, and to a lesser extent along the veins. The expression of ERa and ERb in OL membranes was confirmed by Western analysis of isolated membranes. OL membranes mainly had truncated forms of ERa, 53 and 50 kDa, in addition to some 65 kDa form, whereas ERb was a 54 kDa form. CG4 cells and OLs were pulsed with 17a-and 17b-estradiol for various times and the total lysates were analyzed for phosphorylated kinases. Both 17a-and 17b-estradiol elicited rapid phosphorylation of p42/44MAPK, Akt, and GSK-3b within 8 min. This rapid signaling is consistent with estradiol ligation of a membrane form of ER. Since 17a-estradiol is produced at higher concentrations than 17b-estradiol in the brain of both sexes, signaling via 17a-estradiol-liganded mER may have an important function in OLs. V V C

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

Cited by 234 publications

References 45 publications

Reinnervation of the tibialis anterior following sciatic nerve crush injury: A confocal microscopic study in transgenic mice

Reinnervation of the tibialis anterior following sciatic nerve crush injury: A confocal microscopic study in transgenic mice

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

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

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