Microanatomy of Axon/Glial Signaling during Wallerian Degeneration

Guertin, Amy D.; Zhang, Dan P.; Mak, Kimberley S.; Alberta, John A.; Kim, Haesun A.

doi:10.1523/jneurosci.3766-04.2005

Cited by 165 publications

(141 citation statements)

References 57 publications

(63 reference statements)

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“…In purified Schwann cell cultures, application of neuregulin-1 suppresses basal levels of P 0 expression (Cheng and Mudge, 1996). In myelinating neuronSchwann cell co-cultures, high doses of neuregulin not only inhibit myelination but also induce demyelination (Guertin et al, 2005;Harrisingh et al, 2004;Zanazzi et al, 2001). Furthermore, there is in vivo evidence that demyelination is associated with ErbB2 activation in myelinating Schwann cell microvilli.…”

Section: Erk1/2 and Neuregulin-1mentioning

confidence: 99%

“…Furthermore, there is in vivo evidence that demyelination is associated with ErbB2 activation in myelinating Schwann cell microvilli. These receptors are activated by 10 min after nerve cut but this activation is reduced at 3 h. There is a later rise in activation of ErbB2 receptors on denervated Schwann cells at 5-days post-transection which is maintained at 30 days (Carroll et al, 1997;Cohen et al, 1992;Guertin et al, 2005;Kwon et al, 1997). Levels of neuregulin-1 isoforms also rise from day 3 post-transection (Carroll et al, 1997).…”

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

445

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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Section: Erk1/2 and Neuregulin-1mentioning

confidence: 99%

Section: Erk1/2 and Neuregulin-1mentioning

confidence: 99%

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

Jessen

Mirsky

2008

Glia

445

409

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“…Guertin and coworkers examined the levels of erbB2 activation immediately following sciatic nerve transection and found that there is also an acute and transient increase in the levels of phosphorylated erbB2 and erbB3 in the first hour following injury, which decreases again by 3 h postinjury [80]. In chronically denervated sciatic nerves, expression levels of erbB receptors are much decreased [81].…”

Section: The Expression Of Nrg1 Isoforms and Their Receptors Changes Fomentioning

confidence: 99%

The Role of Neuregulin-1 In the Response To Nerve Injury

Fricker

Bennett

2011

Future Neurol.

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Axons and Schwann cells exist in a highly interdependent relationship: damage to one cell type invariably leads to pathophysiological changes in the other. Greater understanding of communication between these cell types will not only give insight into peripheral nerve development, but also the reaction to and recovery from peripheral nerve injury. The type III isoform of neuregulin-1 (NRG1) has emerged as a key signaling factor that is expressed on axons and, through binding to erbB2/3 receptors on Schwann cells, regulates multiple phases of their development. In adulthood, NRG1 is dispensable for the maintenance of the myelin sheath; however, this factor is required for both axon regeneration and remyelination following nerve injury. The outcome of NRG1 signaling depends on interactions with other pathways within Schwann cells such as Notch, integrin and cAMP signaling. In certain circumstances, this signaling pathway may be maladaptive; for instance, direct binding of Mycobacterium leprae onto erbB2 receptors produces excessive activation and can actually promote demyelination. Attempts to modulate this pathway in order to promote nerve repair will therefore need to give consideration to the exact isoform used, as well as how it is processed and the context in which it is presented to the Schwann cell. Keywordsneuregulin-1; neuropathy; peripheral nerve injury; regeneration; remyelination; repair; Schwann cell Peripheral nerve injury causes significant morbidity and reduced quality of life as a consequence of weakness, sensory loss and neuropathic pain. In total, 6% of the elderly population suffer from peripheral neuropathy [1], which can be caused by metabolic diseases such as diabetes, inherited genetic disorders such as Charcot-Marie-Tooth disease, infectious and inflammatory disorders including Guillan-Barré syndrome and traumatic injury to the nerve (which alone effects up to 300,000 people in Europe per year [1,2]). In contrast to the CNS, peripheral nerves have a significant regenerative capacity [3]; however, in patients, regeneration and the clinical outcome are often poor. Axons regenerate at a rate of approximately 1 mm per day, depending on the site of the lesion. There may be a delay of months if not years before the target zone is re-innervated, and by this time, the target organ and supporting cells may have irreversibly changed, becoming much less receptive to reinnervation. The current approaches to peripheral nerve repair following nerve transection are either to surgically suture the nerve or to bridge the gap between the two cut ends. Financial & competing interests disclosureThe authors have no other rel evant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Europe PMC Funders Group NRGs & the PNSNRGs Neuregulins are a family of growth factors en...

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“…The process of WD can be induced by autoimmune or inflammatory injuries to the axon, as well as by laceration and crush. The term WD now refers to the following events in the distal stump: injury is followed by Ca 2+ influx and axonal protease activation [3][4][5][6][7][8][9][10] ; an important process is the activation and recruitment of macrophages that respond with phagocytosis, leading to the clearance of axonal debris and myelin that is required for axonal repair or regeneration [3][4][5][6][7][8][9][10] .…”

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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Microanatomy of Axon/Glial Signaling during Wallerian Degeneration

Cited by 165 publications

References 57 publications

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

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

The Role of Neuregulin-1 In the Response To Nerve Injury

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

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