Signals regulating myelination in peripheral nerves and the Schwann cell response to injury

Abstract

In peripheral nerves, Schwann cells form myelin, which facilitates the rapid conduction of action potentials along axons in the vertebrate nervous system. Myelinating Schwann cells are derived from neural crest progenitors in a step-wise process that is regulated by extracellular signals and transcription factors. In addition to forming the myelin sheath, Schwann cells orchestrate much of the regenerative response that occurs after injury to peripheral nerves. In response to injury, myelinating Schwann cells dedifferentiate into repair cells that are essential for axonal regeneration, and then redifferentiate into myelinating Schwann cells to restore nerve function. Although this remarkable plasticity has long been recognized, many questions remain unanswered regarding the signaling pathways regulating both myelination and the Schwann cell response to injury.

Figure 1

A simplified model depicting the signaling pathways and transcription factors controlling the initiation, maturation, and maintenance of myelin. (A) Gpr126 and Nrg1-III/ErbB coordinately activate Oct6 and Krox20 expression to initiate myelination. PKA functions downstream of Gpr126 [43], and Sox10 and CREB binding sites are present in the SCE [39,71]. Sox10 and Oct6 binding sites are present in the Krox20 myelinating Schwann cell element (MSE) [72]. Krox20 is maintained independently of Gpr126 after initiation, which likely depends on elements other than the MSE [43]. Downstream of ErbB2, ERK may have context dependent roles that determine whether it synergizes or opposes the effects of Akt. PLC-γ signaling results in Ca²⁺ increases that are reported to activate the MSE via an NFAT dependent mechanism [73] (B) A representation of the stages of myelination during which the pathways and transcription factors shown in A are known to function. Of the factors shown, only Sox10 and Krox20 are required continuously in mature myelinating Schwann cells in the absence of injury [54,74].

Figure 2

A model illustrating the Schwann cell response to peripheral nerve injury. (A) During Wallerian degeneration, Schwann cells distal to the site of injury dedifferentiate (green cells), and participate in the phagocytosis of their own myelin sheaths (small brown circles), and recruit macrophages (yellow cells) to aid in the clearance of myelin debris. Wallerian degeneration is associated with increased activity in multiple signaling pathways in Schwann cells, including JNK/c-Jun, ERK, Notch, and p38. (B) After successful axonal regeneration, remyelination occurs but Schwann cells produce myelin sheaths of reduced thickness. Overexpression of Nrg-III in neurons restores full myelin thickness during regeneration. The conditional deletion of Nrg1-I in Schwann cells results in severe defects in remyelination. See [12] for details.