A role for Schwann cell–derived neuregulin-1 in remyelination

Abstract

After peripheral nerve injury, axons regenerate and become remyelinated by resident Schwann cells. However, myelin repair never results in the original myelin thickness, suggesting insufficient stimulation by neuronal growth factors. Upon testing this hypothesis, we found that axonal neuregulin-1 (NRG1) type III and, unexpectedly, also NRG1 type I restored normal myelination when overexpressed in transgenic mice. This led to the observation that Wallerian degeneration induced de novo NRG1 type I expression in Schwann cells themselves. Mutant mice lacking a functional Nrg1 gene in Schwann cells are fully myelinated but exhibit impaired remyelination in adult life. We suggest a model in which loss of axonal contact triggers denervated Schwann cells to transiently express NRG1 as an autocrine/paracrine signal that promotes Schwann cell differentiation and remyelination.

Neuregulin 1 Role in Schwann Cell Regulation and Potential Applications to Promote Peripheral Nerve Regeneration

“…In these mice, the ectopic neuronal expression of NRG1-type I-β1a does not completely rescue for the absence of SC NRG1, suggesting that NRG1 released by SC is relevant for remyelination. This role is confirmed by the observation that NRG1-type I (both α and β isoforms) is strongly up-regulated following injury (Carroll, Miller, Frohnert, Kim, & Corbett, 1997;Ronchi et al, 2013;Stassart et al, 2013).…”

“…Neuronal transmembrane NRG1-type III-β1a overexpression induces hyper-myelination (Michailov et al, 2004), converts unmyelinated axons of sympathetic neurons to myelination (Taveggia et al, 2005), improves remyelination after peripheral nerve injury (Stassart et al, 2013).…”

“…Neuronal soluble NRG1-type I-β1a overexpression does not alter myelination (Michailov et al, 2004), but improves remyelination after peripheral nerve injury (Stassart et al, 2013). These authors demonstrate that NRG1 produced by SC is not necessary for myelination, but it is strongly involved in remyelination, which is strongly impaired after nerve crush in mice lacking SC NRG1, resulting in severe hypo-myelination.…”

“…Following nerve injury, SC respond to axonal damage up-regulating NRG1-type I/II (Carroll et al, 1997;Ronchi et al, 2013;Stassart et al, 2013) and activating ERK signalling pathway (Harrisingh et al, 2004). Accordingly, it has been shown that activation of the ERK-signalling pathway in myelinating SC drives them back to a dedifferentiated state, that is reversible: as soon as ERK signal diminishes, SC respond to axonal signals and redifferentiate (Napoli et al, 2012).…”

“…The different NRG1 isoforms play an important role in this process, thanks to their ability to stimulate dedifferentiation, proliferation and differentiation of SC in vitro (Stassart et al, 2013).…”