Glutamate signals through mGluR2 to control Schwann cell differentiation and proliferation.

Fuminori Saitoh,Shinji Tokunaga,Hiroki Fujieda,Shuji Wakatsuki,Toshiyuki Araki

doi:10.1038/srep29856

Abstract

Rapid saltatory nerve conduction is facilitated by myelin structure, which is produced by Schwann cells (SC) in the peripheral nervous system (PNS). Proper development and degeneration/regeneration after injury requires regulated phenotypic changes of SC. We have previously shown that glutamate can induce SC proliferation in culture. Here we show that glutamate signals through metabotropic glutamate receptor 2 (mGluR2) to induce Erk phosphorylation in SC. mGluR2-elicited Erk phosphorylation requires ErbB2/3 receptor tyrosine kinase phosphorylation to limit the signaling cascade that promotes phosphorylation of Erk, but not Akt. We found that Gβγ and Src are involved in subcellular signaling downstream of mGluR2. We also found that glutamate can transform myelinating SC to proliferating SC, while inhibition of mGluR2 signaling can inhibit demyelination of injured nerves in vivo. These data suggest pathophysiological significance of mGluR2 signaling in PNS and its possible therapeutic importance to combat demyelinating disorders including Charcot-Marie-Tooth disease.

Highlights

Rapid saltatory conduction of electrical signals along the distance of an axon is facilitated by myelin, a lipid-rich ionic insulator that wraps around the axon[1,2]
We showed that forced expression of glutamine synthetase (GS) resulted in increased myelination in vitro, and that glutamate along with an metabotropic glutamate receptor (mGluR) agonist promotes Schwann cells (SC) proliferation
To show that the myelination-promoting effect of GS expression in SC is mediated by mGluR signaling, we first examined the effects of mGluR inhibitors on SC myelination and glutamate-induced SC proliferation in vitro

Summary

Introduction

Rapid saltatory conduction of electrical signals along the distance of an axon is facilitated by myelin, a lipid-rich ionic insulator that wraps around the axon[1,2]. CAMP-stimulating agents increase the potency of Nrg[1]; cAMP can upregulate the expression of a number of myelin genes such as: myelin protein zero (P0) and the transcription factor SCIP/Oct-6/Tst-1, which are essential regulators of SC differentiation into a myelinating phenotype[11]. It has become increasingly clear that the undifferentiated/differentiated phenotypes of SC are tightly regulated by a cascade of intracellular signaling events, and an orchestrated series of gene expression pathways of regulatory proteins and molecules found on the cell surface and extracellular matrix[13,14]. For quantification in (E) the numbers of myelination profiles visualized by MBP staining and the intensity of NFM immunoreactivity were analyzed from five randomly selected fields under a microscope using a 20x objective lens (mean ± SD, n = 3). Asterisks indicate significant difference from control (Student’s t test, *p < 0.05)

Methods

Results

Conclusion