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

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.

The Eph receptor A4 plays a role in demyelination and depression-related behavior

“…The Ephrin A4 receptor (EphA4) is a member of the Eph family of receptor tyrosine kinases. Activation of EphA4 decreases myelination in both the CNS (central nervous system) and PNS (peripheral nervous system) (27)(28)(29). EphA4 has also been shown to modulate synaptic plasticity (30), axon guidance (31), and neurogenesis (32), and all of these neural functions have previously been implicated in the pathobiology of depression (33,34).…”

Unraveling Axon Guidance during Axotomy and Regeneration

“…On the other hand, early after injury, EphA4 is upregulated in Schwann cells, inhibiting differentiation, and increasing proliferation, which is needed for preventing myelination and improving migration. After this early response, EphA4 is downregulated, coincident with differentiation and new axons myelination [ 164 ]. The maintenance of the nerve bridge morphology is in part due to peripheral macrophages expressing the repulsive cue Slit3 ( Figure 2 B).…”

“…srGAP1 and srGAP3(srGAP1/3) are upregulated in the adult mice DRG after nerve transection, in neurons and astrocytes [ 199 ], while Glypican-1 was also upregulated in DRG cells after nerve transection, dorsal column transection, and dorsal rhizotomy [ 200 ] ( Table 2 ). Finally, EphA4 is upregulated after sciatic nerve crush, followed by a drastic downregulation [ 164 ] ( Table 2 ). It has been described that EphA4 increases Schwann cells proliferation while inhibiting differentiation and thus, decreases myelination [ 164 ].…”

“…Finally, EphA4 is upregulated after sciatic nerve crush, followed by a drastic downregulation [ 164 ] ( Table 2 ). It has been described that EphA4 increases Schwann cells proliferation while inhibiting differentiation and thus, decreases myelination [ 164 ]. Therefore, the initially observed upregulation of EphA4 levels could be related to a proliferative process of Schwann cells after peripheral injury, and the following downregulation with differentiation and myelinization.…”

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

“…Those carriers are mostly used for siRNAs. For instance, a cholesterol-modified siRNA against EphA4 was used to enhance axon regeneration in rats [110]. siRNAs embedded in silicon porous particles, called SIMPs, have been used to provide EphA2 silencing over 3 weeks in a mouse model of ovarian cancer [111].…”