c-Jun is a negative regulator of myelination

Parkinson, DB; Bhaskaran, A; Arthur‐Farraj, Peter; Noon, Luke A.; Woodhoo, Ashwin; Lloyd, Alyson; Feltri, M. Laura; Wrabetz, Lawrence; Behrens, Axel; Mirsky, Rhona; Jessen, KR

doi:10.1083/jcb.200803013

Cited by 366 publications

(511 citation statements)

References 57 publications

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“…Old mice also showed increased cJun expression and phosphorylation. These pathway changes may indicate a persistent repair attempt in intact old nerves (Napoli et al, 2012; Parkinson et al, 2008). …”

Section: Resultsmentioning

confidence: 99%

Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.

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Section: Resultsmentioning

confidence: 99%

Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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“…Conversely, myelin gene expression is increased in c-Jun null Schwann cells . c-Jun is rapidly upregulated after nerve injury, a procedure that triggers Schwann cell dedifferentiation (De Felipe and Hunt, 1994;Parkinson et al, 2008;Shy et al, 1996). To determine the function of c-Jun under these conditions, we generated a conditional knockout of c-Jun in Schwann cells (Arthur-Farraj et al, 2007).…”

Section: C-junmentioning

confidence: 99%

“…Enforced Sox-2 expression inhibits activation of myelin genes by Krox-20 or cAMP elevation, and inhibits myelination in co-cultures. It is upregulated following injury and co-expressed with c-Jun in the nuclei of dedifferentiating cells (Le et al, 2005;Parkinson et al, 2008).…”

Section: Sox-2mentioning

confidence: 99%

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

Jessen

Mirsky

2008

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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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“…Many genes and related proteins are differentially expressed during WD, the latter including cytokines, neurotrophic factors, axonal myelin and cell adhesion molecules [11][12][13][14][15][16][17][18] . The development of tissue biochemistry and molecular biology, together with improvements in microscopic resolution, has largely facilitated the understanding of the significance of WD in the processes of nerve degeneration and subsequent repair/regeneration [11][12][13][14][15][16][17][18] . Understanding the molecular mechanisms of axonal debris and myelin clearance after processed using GeneSpring GCOS1.2 software.…”

Section: Introductionmentioning

confidence: 99%

Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat

Yao

Shen

et al. 2013

Neurosci. Bull.

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Wallerian degeneration (WD) remains an important research topic. Many genes are differentially expressed during the process of WD, but the precise mechanisms responsible for these differentiations are not completely understood. In this study, we used microarrays to analyze the expression changes of the distal nerve stump at 0, 1, 4, 7, 14, 21 and 28 days after sciatic nerve injury in rats. The data revealed 6 076 differentially-expressed genes, with 23 types of expression, specifically enriched in genes associated with nerve development and axonogenesis, cytokine biosynthesis, cell differentiation, cytokine/chemokine production, neuron differentiation, cytokinesis, phosphorylation and axon regeneration. Kyoto Encyclopedia of Genes and Genomes pathway analysis gave findings related mainly to the MAPK signaling pathway, the Jak-STAT signaling pathway, the cell cycle, cytokine-cytokine receptor interaction, the p53 signaling pathway and the Wnt signaling pathway. Some key factors were NGF, MAG, CNTF, CTNNA2, p53, JAK2, PLCB1, STAT3, BDNF, PRKC, collagen II, FGF, THBS4, TNC and c-Src, which were further validated by real-time quantitative PCR, Western blot, and immunohistochemistry. Our findings contribute to a better understanding of the functional analysis of differentially-expressed genes in WD and may shed light on the molecular mechanisms of nerve degeneration and regeneration.

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c-Jun is a negative regulator of myelination

Cited by 366 publications

References 57 publications

Inflammaging impairs peripheral nerve maintenance and regeneration

Inflammaging impairs peripheral nerve maintenance and regeneration

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

Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat

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