Neuregulin 1 isoforms could be an effective therapeutic candidate to promote peripheral nerve regeneration

Traumatic injuries of peripheral nerves represent common casualties and their social impact is considerably high. Although peripheral nerves retain a good regeneration potential, the clinical outcome after nerve lesion is far from being satisfactory and functional recovery is almost never complete, especially in the case of large nerve defects, that result in loss or diminished sensitivity and/or motor activity of the innervated target organs. Therefore, to improve the outcome after nerve damage, or in peripheral neuropathies, there is a need for further research in nerve repair and regeneration to identify factors that promote axonal regrowth, remyelination and target reinnervation. Among the different factors involved in these processes (Taveggia et al., 2010; Pereira et al., 2012), stands out neuregulin 1 (NRG1), a factor which plays a role both in the myelination occurring during development (Lemke, 2006) and in the response to peripheral nerve injury (Syed and Kim, 2010; Fricker and Bennett, 2011). NRG1 is a pleiotropic factor characterized by the existence of numerous isoforms arising from alternative splicing of exons that confer to the protein with deeply different characteristics (Falls, 2003; Mei and Xiong, 2008). NRG1 can be produced as a secreted or as a transmembrane protein ready to interact with its receptor, or as a transmembrane pro-protein that needs a proteolytic cleavage to release a soluble fragment or to protrude its receptor binding domain in the extracellular environment (Figure 1). According to its structure, NRG1 signals in a paracrine, autocrine or juxtacrine manner; moreover, juxtacrine interactions can signal both in a forward and reverse manner due to the production of a fragment containing the intracellular domain (ICD, Figure 1B) that can translocate into the nucleus and influence gene transcription (Bao et al., 2003; Bao et al., 2004; Chen et al., 2010). NRG1 interacts directly with two of the four members of the tyrosine kinase receptor family ErbB: ErbB4, that signals as homo or heterodimer, and ErbB3, that forms a heterodimer with ErbB2. Figure 1 Structure of soluble or transmembrane neuregulin 1 (NRG1) isoforms. In the peripheral nervous system, NRG1 soluble isoforms are mainly released by Schwann cells, while transmembrane isoforms are mainly expressed by the axon and both interact with the heterodimer receptor ErbB2-ErbB3, generally expressed by Schwann cells. NRG1 plays an important role both in the myelination occurring during development and in the different phases occurring after injury in the peripheral nerve: axon degeneration, axon regrowth, remyelination and target reinnervation (Taveggia et al., 2010; Fricker and Bennett, 2011; Pereira et al., 2012; Salzer, 2012; Gambarotta et al., 2013; Heermann and Schwab, 2013). These processes respond to different cues, as can be inferred from the analysis of transgenic mice models summarized in Figure 2. The difference between the myelination process occurring during development and the regeneration process occurring after nerve injury is underlined by the fact that soluble NRG1 isoforms play an important role after nerve injury, while their lack seems irrelevant during development. Figure 2 The role played by soluble and transmembrane neuregulin 1 (NRG1) isoforms in the myelination occurring during development and in the different phases occurring after nerve injury (axon degeneration, axon regeneration, remyelination and target reinnervation) .