Neuregulin Facilitates Nerve Regeneration by Speeding Schwann Cell Migration via ErbB2/3-Dependent FAK Pathway

Chang, Hong-Yeh; Shyu, Ming‐Kwang; Tseng, Guo‐Fang; Liu, Chiung‐Hui; Chang, Hung Shuo; Lan, Chyn-Tair; Hsu, Wen Ming; Liao, Wen Chieh

doi:10.1371/journal.pone.0053444

Cited by 37 publications

(27 citation statements)

References 35 publications

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“…These findings are consistent with earlier report that MeB12 promotes the transport of axonal cytoskeleton [20]. The large increase of S100, by and large a Schwann cell marker [10,24], in the recipient nerves of the MeB12-treated group also echoed the enhancement on axonal growth as Schwann cells can induce collateral sprouting of intact axons [31] and are critical to peripheral nerve growth after ESN [25]. Furthermore, it is consistent with earlier reports that MeB12 enhances Schwann cell proliferation and migration [21,34] as well as maturation [24].…”

Section: Discussionsupporting

confidence: 91%

“…We examined the expressions of several axonal growth-related markers (Schwann cell marker S100 [24,25], axonal growth marker growth-associated protein 43 (Gap43), and neuron specific cytoskeleton marker βIII tubulin) in the nerve proximal and distal to the neurorrhaphy site to investigate the readiness of reinnervation of target muscle a month after surgery. Electrophysiological, morphological and behavioral means were used to assess the outcome of the combination of drugs up to 6 months following coaptation.…”

Section: Introductionmentioning

confidence: 99%

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Methylcobalamin Facilitates Collateral Sprouting of Donor Axons and Innervation of Recipient Muscle in End-to-Side Neurorrhaphy in Rats

et al. 2013

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Using ulnar nerve as donor and musculocutaneous nerve as recipient we found earlier that end-to-side neurorrhaphy resulted in weak functional reinnervation after lengthy survival. End-to-side neurorrhaphy however is the sole choice of nerve repair at times and has the advantage of conserving donor nerve function. Here, we investigated whether myelination-enhancing agent methylcobalamin and motoneuron trophic factor pleiotrophin enhances the recovery after end-to-side neurorrhaphy. Methylcobalamin significantly increased the expression of growth associated protein 43 and S100 protein and βIII tubulin in musculocutaneous nerve 1 month after neurorrhaphy suggesting the ingrowth of ulnar axonal sprouts in reactive Schwann cell environment. Upper limb functional test, compound muscle action potential measurements, motor end plate counts, and axon and myelin analyses showed that methylcobalamin treatment alone or with pleiotrophin improved the recovery significantly, 3 and 6 months post-surgery. There were fewer axons, closer in number to that of the intact recipient nerve, found in the distal repaired nerve of the methylcobalamin-treated than that of the vehicle control, suggesting that methylcobalamin facilitates axonal maturation and eliminates supernumerary sprouts. In conclusion, our results showed that methylcobalamin does indeed enhance the recovery of peripheral nerve repaired in end-to-side configuration.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Methylcobalamin Facilitates Collateral Sprouting of Donor Axons and Innervation of Recipient Muscle in End-to-Side Neurorrhaphy in Rats

et al. 2013

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“…Isoforms of axonal- and Schwann cell-derived Nrg1 have been implicated in the regulation of peripheral nerve demyelination and regeneration following injury (Chang et al, 2013; Fricker et al, 2011; Stassart et al, 2013), Significant changes in Nrg1 expression were not detected in Cx32KO nerves relative to WT at any time points examined. While regulation of Nrg1 receptors ErbB2 and ErbB3 are essential to peripheral nerve responses to injury (Mukhatyar et al, 2013; Nicolino et al, 2009), the probes for ErbB2 and ErbB3 were not present on Illumina Mouse Ref8-v2 chips, precluding the ability to address regulation of ErbB2 and ErbB3 genes in these studies.…”

Section: Discussionmentioning

confidence: 92%

Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: Uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves

Freidin

Asche-Godin

Abrams

2015

Experimental Neurology

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X-linked Charcot–Marie–Tooth disease (CMT1X) is an inherited peripheral neuropathy caused by mutations in GJB1, the human gene for Connexin32 (Cx32). This present study uses Ilumina Ref8-v2 BeadArray to examine the expression profiles of injured and uninjured sciatic nerves at 5, 7, and 14 days post-crush injury (dpi) from Wild Type (WT) and Cx32-knockout (Cx32KO) mice to identify the genes and signaling pathways that are dysregulated in the absence of Schwann cell Cx32. Given the assumption that loss of Schwann cell Cx32 disrupts the regeneration and maintenance of myelinated nerve leading to a demyelinating neuropathy in CMT1X, we initially hypothesized that nerve crush injury would result in significant increases in differential gene expression in Cx32KO mice relative to WT nerves. However, microarray analysis revealed a striking collapse in the number of differentially expressed genes at 5 and 7 dpi in Cx32KO nerves relative to WT, while uninjured and 14dpi time points showed large numbers of differentially regulated genes. Further comparisons within each genotype showed limited changes in Cx32KO gene expression following crush injury when compared to uninjured Cx32KO nerves. By contrast, WT nerves exhibited robust changes in gene expression at 5 and 7dpi with no significant differences in gene expression by 14dpi relative to uninjured WT nerve samples. Taken together, these data suggest the gene expression profile in uninjured Cx32KO sciatic nerve strongly resembles that of a WT nerve following injury and that loss of Schwann cell Cx32 leads to a basal state of gene expression similar to that of an injured WT nerve. These findings support a role for Cx32 in non-myelinating and regenerating populations of Schwann cells in normal axonal maintenance in re-myelination, and regeneration of peripheral nerve following injury. Disruption of Schwann cell-axonal communication in CMT1X may cause dysregulation of signaling pathways that are essential for the maintenance of intact myelinated peripheral nerves and to establish the necessary conditions for successful regeneration and remyelination following nerve injury.

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“…The in vivo model of PNI was performed by means of end‐to‐side neurorrhaphy (ESN) as described in our previous studies . Briefly, after deeply anesthetized with intraperitoneal injection of 7% chloral hydrate (Sigma‐Aldrich, St. Louis, MO, USA), rats were placed on the surgical microscope and an incision was made along the left mid‐clavicular line to expose the left brachial plexus.…”

Section: Methodsmentioning

confidence: 99%

Proliferative effects of melatonin on Schwann cells: implication for nerve regeneration following peripheral nerve injury

Chang

Liu

Hsu

et al. 2014

Journal of Pineal Research

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Activation of proliferation of Schwann cells is crucial for axonal guidance and successful nerve regeneration following peripheral nerve injury (PNI). Considering melatonin plays an important role in proliferative regulation of central glial cells, the present study determined whether melatonin can effectively promote Schwann cell proliferation and improve nerve regeneration after PNI. The spontaneous immortalized rat Schwann cell line (RSC 96 cells) was first analyzed by quantitative polymerase chain reaction (QPCR) to detect the potential existence of melatonin receptors. The melatonin receptor-mediated signaling responsible for proliferation was examined by measuring the phosphorylation of extracellular signal-regulated kinases (ERK1/2) pathway. The in vivo model of PNI was performed by the end-to-side neurorrhaphy. The quantity of Schwann cells as well as the number of re-innervated motor end plates (MEP) on target muscles was examined to represent the functional recovery of injured nerves. QPCR results indicated that MT1 is the dominant receptor in Schwann cells. Immunoblotting and proliferation assay revealed an enhanced phosphorylation of ERK1/2 and increased number of RSC 96 cells following melatonin administration. Nonselective melatonin receptor antagonist (luzindole) treatment significantly suppressed all the above findings, suggesting that the proliferative effects of melatonin were mediated by a receptor-dependent pathway. In vivo results corresponded well with in vitro findings in which melatonin effectively increased the amount of proliferated Schwann cells and re-innervated MEP on target muscles following PNI. As melatonin successfully improves nerve regeneration by promoting Schwann cell proliferation, therapeutic use of melatonin may thus serve as a promising strategy to counteract the PNI-induced neuronal disability.

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Neuregulin Facilitates Nerve Regeneration by Speeding Schwann Cell Migration via ErbB2/3-Dependent FAK Pathway

Cited by 37 publications

References 35 publications

Methylcobalamin Facilitates Collateral Sprouting of Donor Axons and Innervation of Recipient Muscle in End-to-Side Neurorrhaphy in Rats

Methylcobalamin Facilitates Collateral Sprouting of Donor Axons and Innervation of Recipient Muscle in End-to-Side Neurorrhaphy in Rats

Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: Uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves

Proliferative effects of melatonin on Schwann cells: implication for nerve regeneration following peripheral nerve injury

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