Inhibition of Ras extracellular‐signal‐regulated kinase (ERK) mediated signaling promotes ciliary neurotrophic factor (CNTF) expression in Schwann cells

Abstract

Ciliary neurotrophic factor (CNTF) can prevent injury-induced motor neuron death. However, it is also evident that expression of CNTF in Schwann cells is suppressed during nerve regeneration. In this report, we have addressed the mechanism underlying the down-regulation of CNTF expression in injured nerves using a mouse Schwann cell line IMS32 and mouse sciatic nerve. In IMS32 cells, activation of the Ras extracellular-signal-regulated kinase (ERK) pathway by adenoviral vector-mediated expression of dominant active MEK1 did not alter a basal level of CNTF expression, whereas inhibition of the Ras-ERK pathway by using adenoviral vectors resulted in a marked increase in CNTF expression. This inverse relation between before and after axotomy was also observed in mouse sciatic nerve. In the axotomized sciatic nerve, the phosphorylated ERK was markedly increased; in contrast, the expression of CNTF was markedly decreased. These ®ndings suggest that an inactive state of ERK is crucial for the CNTF expression in Schwann cells, and that activation of ERK following nerve injury critically in¯uences the expression of CNTF. This might well explain why CNTF is highly expressed in quiescent Schwann cells in the peripheral nervous system, and also why CNTF is not abundant in axotomized nerves or cultured Schwann cells in which the proliferation signal is obviously active.

Lentiviral-mediated transfer of CNTF to schwann cells within reconstructed peripheral nerve grafts enhances adult retinal ganglion cell survival and axonal regeneration

“…We also saw CNTF mRNA expression in normal cellular PNs (data not shown). Our data suggest that the level of endogenous CNTF is low in cultured adult SCs, a result consistent with some previous reports [23,24].…”

Activation of extracellular-signal-regulated kinase-1/2 precedes and is required for injury-induced Schwann cell proliferation

“…Previous papers have shown an increase of p-Erk1/2 in the immediate proximity of a peripheral nerve lesion [5,[9][10][11][12]. The localization of p-Erk1/2, however, seems to differ.…”

“…Activation of MAPKs occurs by phosphorylation of the signalling proteins in the cascade [7,8]. p-Erk1/2 accumulates in Schwann cells surrounding the site of nerve transection [9][10][11][12]. We therefore assumed that activation of Erk1/2 would be associated with a proliferative response.…”

Mesenchymal Stem Cells and Umbilical Cord as Sources for Schwann Cell Differentiation: their Potential in Peripheral Nerve Repair

“…Schwann cells secrete a large variety of neurotrophic factors, including neurotrophins, transforming growth factor, basic fibroblast growth factor (bFGF), fibroblast growth factor-5, glial cell line-derived neurotrophic factor, osteopontin, IL-1β, IL-6 and leukemia inhibitory factor. All of these factors are thought to contribute to successful axonal regeneration [5,[52][53][54]. Particularly, neurotrophins and their downstream Ras/mitogen activated protein kinase and phosphoinositide-3-kinase/Akt pathways are critical for both axonal growth and neuron survival in the PNS [55,56].…”