EphA4 Negatively Regulates Myelination by Inhibiting Schwann Cell Differentiation in the Peripheral Nervous System.

Ruyue Chen,Xiaoming Yang,Shiying Li,Bin Zhang,Yun Gu,Shengran Wang,Shuangxi Bao

doi:10.3389/fnins.2019.01191

Ruyue Chen, Xiaoming Yang + Show 5 more

Open Access

https://doi.org/10.3389/fnins.2019.01191

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Abstract

Myelin plays a crucial role in axon function recovery following nerve damage, and the interaction between Schwann cells (SCs) and regenerating axons profoundly affects myelin formation. Eph receptor A4 (EphA4), a member of the Eph tyrosine kinase receptor family, regulates cell-cell interactions via its ligand ephrins. However, our current knowledge on how EphA4 regulates the formation of myelin sheaths remains limited. In order to explore the roles of EphA4 in myelination in the peripheral nervous system, we used a combination of (1) a co-culture model of dorsal root ganglion (DRG) explants and SCs, (2) a SC differentiation model induced by db-cAMP, and (3) a regeneration model of crushed sciatic nerves in rats. Our results demonstrated that EphA4 inhibited myelination by inhibiting SC differentiation and facilitating SC proliferation in vitro. The in vivo experiments revealed that EphA4 expression in SCs is upregulated following nerve crush injury and then downregulated during remyelination. Moreover, silencing of EphA4 by siRNA or overexpression of EphA4 by genetic manipulation can accelerate or slow down nerve remyelination in crushed sciatic nerves. Taken together, our results suggest that EphA4 may negatively regulate myelination by abrogating SC differentiation.

Highlights

Myelin is a lamellar structure formed by glial cells entangled with neuronal axons, mainly composed of oligodendrocytes in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS)
The results showed that, compared to other Eph family receptors, the Eph receptor A4 (EphA4) gene was highly expressed in SCs (Figure 1A) and dorsal root ganglion (DRG) neurons (Figure 1B), and EphA4 shows similar expression pattern with Krox20/Egr2 in the nerve injury model (Supplementary Figure 1)
E, EphA4 was mainly localized in the soma of DRG neurons and whole SCs, consistent with the in vitro finding. These results demonstrated that EphA4 is expressed and localized in the entire SC

Summary

Introduction

Myelin is a lamellar structure formed by glial cells entangled with neuronal axons, mainly composed of oligodendrocytes in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS). Eph/Ephrin is an important mediator of bidirectional signaling between axons and glial cells in the nervous system, involved in multiple processes such as astrocyte activation and scar formation, axon guidance, axonal regeneration, synaptic plasticity, and myelination (Linneberg et al, 2015). Activating Ephrins in zebrafish neuronal axons can induce EphA4 expression in oligodendrocytes, which affects the contact between axons and glial cells, thereby inhibiting myelin formation (Harboe et al, 2018). These studies suggest a role for EphA4 in regulating myelination in both the CNS and PNS. The mechanisms by which EphA4 regulates formation and maintenance of myelin sheaths remain poorly understood

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