Cooperative interaction of hepatocyte growth factor and neuregulin regulates Schwann cell migration and proliferation through Grb2-associated binder-2 in peripheral nerve repair

Abstract

The sequential reactive changes in Schwann cell phenotypes in transected peripheral nerves, including dedifferentiation, proliferation and migration, are essential for nerve repair. Even though the injury-induced migratory and proliferative behaviors of Schwann cells resemble epithelial and mesenchymal transition (EMT) in tumors, the molecular mechanisms underlying this phenotypic change of Schwann cells are still unclear. Here we show that the reactive Schwann cells exhibit migratory features dependent on the expression of a scaffolding oncoprotein Grb2-associated binder-2 (Gab2), which was transcriptionally induced by neuregulin 1-ErbB2 signaling following nerve injury. Injury-induced Gab2 expression was dependent on c-Jun, a transcription factor critical to a Schwann cell reprograming into a repair-type cell. Interestingly, the injury-induced activation (tyrosine phosphorylation) of Gab2 in Schwann cells was regulated by an EMT signal, the hepatocyte growth factor-c-Met signaling, but not by neuregulin 1. Gab2 knockout mice exhibited a deficit in nerve repair after nerve transection due to limited Schwann cell migration. Furthermore, Gab2 was required for the proliferation of Schwann cells following nerve injury and in vitro, and was over-expressed in human Schwann cell-derived tumors. In contrast, the tyrosine phosphorylation of Gab1 after nerve injury was principally regulated by the neuregulin 1-ErbB2 signaling and was indispensable for remyelination after crush injury, but not for the proliferation and migration of Schwann cells. Our findings indicate that Gab1 and Gab2 in Schwann cells are nonredundant and play a crucial role in peripheral nerve repair.

Serum CXCL13 reflects local B-cell mediated inflammatory demyelinating peripheral neuropathy

“…Firstly, as revealed in B7-2KO mice, CXCL13 may be involved in the pro-inflammatory condition associated with local immune activation within neuropathic nerves. Secondly, even though HGF, TNF-α and CCLs may represent the local inflammatory condition in nerves, these cytokines could be induced as a result of the activation of innate immunity during WD 6,26,27 ; hence, they cannot specifically represent the pro-inflammatory condition in nerves. Finally, we found no significant increase in CXCL13 serum levels in patients with AMAN, an axonal form of GBS.…”

p75 and neural cell adhesion molecule 1 can identify pathologic Schwann cells in peripheral neuropathies

“…Primary SC culture from neonatal rat sciatic nerves was performed as previously reported . For biochemistry and collection of conditioned medium, cells were used at 2–4 generations.…”

“…Alexa Fluor 488 or Cy3‐conjugated antibodies were used for the secondary antibodies. Immunofluorescence staining and western blot analysis were performed as previously described . The sources of antibodies and reagents will be provided upon request.…”

Hepatocyte Growth Factor (HGF) Promotes Peripheral Nerve Regeneration by Activating Repair Schwann Cells

“…In the case of PNS, HGF can enhance survival and axon outgrowth of cultured motor neurons 16 – 19 , and it is also known to interact with NGF to exert neurotrophic effects on sensory neurons 20 . Recently, it has been reported that Gab2 protein is required for the migration and proliferation of SCs and HGF could induce the activation of Gab2 to show such cellular effects 21 . However, whether c-met receptor has any role in peripheral nerve injury is largely unknown.…”