Axonal Neuregulin 1 Type III Activates NF-κB in Schwann Cells during Myelin Formation

Allison S Limpert,Bruce D Carter

doi:10.1074/jbc.m109.098780

Allison S Limpert, Bruce D Carter

Open Access

https://doi.org/10.1074/jbc.m109.098780

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Abstract

The formation of myelin requires a series of complex signaling events initiated by the axon to surrounding glial cells, which ultimately respond by tightly wrapping the axon with layers of specialized plasma membrane thereby allowing for saltatory conduction. Activation of the transcription factor NF-kappaB in Schwann cells has been suggested to be critical for these cells to differentiate into a myelinating phenotype; however, the mechanisms by which it is activated have yet to be elucidated. Here, we demonstrate that axonal membranes are sufficient to promote NF-kappaB activation in cultured Schwann cells and identify neuregulin 1 (NRG1), specifically the membrane-bound type III isoform, as the signal responsible for activating this transcription factor. Surprisingly, neither membrane-bound type I nor the soluble NRG1 EGF domain could activate NF-kappaB, indicating that type III induces a qualitatively unique signal. The transcriptional activity of NF-kappaB was significantly enhanced by treatment with forskolin, indicating these two signals converge for maximal activation. Both ErbB2 and -3 receptors were required for transducing the NRG1 signal, because gene deletion of ErbB3 in Schwann cells or treatment with the ErbB2 selective inhibitor, PKI-166, prevented the stimulation of NF-kappaB by axonal membranes. Finally, PKI-166 blocked the activation of the transcription factor in myelinating neuron/Schwann cell co-cultures and in vivo, in developing sciatic nerves. Taken together, these data establish NRG1 type III as the activator of NF-kappaB during myelin formation.

Highlights

One of the key signals implicated in Schwann cell reprogramming into a myelinating phenotype is the activation of the transcription factor NF-␬B [1]
The protein kinase A (PKA) inhibitor, H89, had no effect on either the axonal stimulation of NF-␬B-DNA binding (Fig. 1G) or transcriptional activity (Fig. 1F). These results indicate that an axon membrane-associated factor can stimulate NF-␬B binding to DNA, but an additional signal is required for maximal transcriptional activity
ErbB2 Mediates the Activation of NF-␬B during Myelin Formation—The preceding results demonstrate that membrane-bound neuregulin 1 (NRG1) type III is able to stimulate NF-␬B in purified Schwann cells; we sought to determine whether neuregulin signaling was responsible for the activation of this transcription factor during peripheral myelin formation

Summary

Introduction

One of the key signals implicated in Schwann cell reprogramming into a myelinating phenotype is the activation of the transcription factor NF-␬B [1]. We report here that membrane-bound type III NRG1 is the axonal signal responsible for initiating NF-␬B activation in Schwann cells during myelination. Treatment of Schwann cells with the EGF domain (GGF) failed to elicit NF-␬B activation (Fig. 2C), suggesting that membrane-bound, type III NRG1 is uniquely able to stimulate this transcription factor.

Results

Conclusion