ErbB2 Signaling in Schwann Cells Is Mostly Dispensable for Maintenance of Myelinated Peripheral Nerves and Proliferation of Adult Schwann Cells after Injury

Atanasoski, Suzana; Scherer, Steven S.; Sirkowski, Erich; Leone, Dino P.; Garratt, Alistair N.; Birchmeier, Carmen; Suter, Ueli

doi:10.1523/jneurosci.4594-05.2006

Cited by 109 publications

(99 citation statements)

References 59 publications

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“…Despite its importance in developmental myelination, Nrg1/ErbB signaling is not required for the maintenance of the myelin sheath in adulthood (Atanasoski et al, 2006;Fricker et al, 2011;Fricker et al, 2013). Injury radically alters the communication between axons, glia and immune cells, and effective signaling between these cells is crucial for successful nerve repair (Fawcett and Keynes, 1990;Scheib and Hoke, 2013).…”

Section: Nrg1 and Remyelination After Injurymentioning

confidence: 99%

“…Erbin expression increases in distal nerve after injury, and Erbin mutant mice display impaired remyelination and functional recovery (Liang et al, 2012). The early phases of the injury response are not Nrg1 dependent: Myelin clearance is not delayed when Nrg1 is lacking, and Schwann cell proliferation during regeneration was not impaired in the absence of Nrg1 signaling (Atanasoski et al, 2006;Fricker et al, 2013). Finally, the inflammatory response is not Nrg1-dependent .…”

Section: Nrg1 and Remyelination After Injurymentioning

confidence: 99%

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Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Birchmeier

Bennett

2016

Current Topics in Developmental Biology

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Myelin is essential for rapid and accurate conduction of electrical impulses by axons in the central and peripheral nervous system. Myelin is formed in the early postnatal period, and developmental myelination in the peripheral nervous system (PNS) depends on axonal signals provided by Nrg1/ErbB receptors. In addition, Nrg1 is required for effective nerve repair and remyelination in adulthood. We discuss here similarities and differences in Nrg1/ErbB functions in developmental myelination and remyelination after nerve injury.

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Section: Nrg1 and Remyelination After Injurymentioning

confidence: 99%

Section: Nrg1 and Remyelination After Injurymentioning

confidence: 99%

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Birchmeier

Bennett

2016

Current Topics in Developmental Biology

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“…Although a role in dedifferentiation therefore remains unclear, neuregulin-1 appears not to be required for the burst of Schwann cell proliferation that follows nerve injury (Atanasoski et al, 2006). Furthermore, cut out of ErbB2 receptors in Schwann cells in uninjured adult nerves, using cre-lox technology, does not result in myelin breakdown, indicating that neuregulin-1 signaling is not needed for myelin stability (Atanasoski et al, 2006).…”

Section: Erk1/2 and Neuregulin-1mentioning

confidence: 99%

“…Furthermore, cut out of ErbB2 receptors in Schwann cells in uninjured adult nerves, using cre-lox technology, does not result in myelin breakdown, indicating that neuregulin-1 signaling is not needed for myelin stability (Atanasoski et al, 2006).…”

Section: Erk1/2 and Neuregulin-1mentioning

confidence: 99%

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

Jessen

Mirsky

2008

Glia

457

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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“…There is now clear evidence that ongoing NRG1 signaling is not required for maintenance of the myelin sheath in adulthood. Conditional ablation of NRG1 in peripheral axons or the erbB2 receptor in SCs has no effect on axon or myelin integrity in naive adult nerves [75]. This is in contrast to Krox 20, which is essential for myelin maintenance in adulthood [76].…”

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confidence: 91%

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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ErbB2 Signaling in Schwann Cells Is Mostly Dispensable for Maintenance of Myelinated Peripheral Nerves and Proliferation of Adult Schwann Cells after Injury

Cited by 109 publications

References 59 publications

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

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

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

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