The neuron-glia signal beta-neuregulin promotes Schwann cell motility via the MAPK pathway

Neuregulins constitute a family of related growth factors that play important roles in Schwann cell development and maturation. We investigated the involvement of beta-neuregulin in Schwann cell migration, using a simple in vitro bioassay. Pure Schwann cells were prepared from the sciatic nerves of 5-day-old rats and were grown in defined medium, with or without serum, until a monolayer of confluent cells was formed. A cell-free area was then generated by inflicting a scratch resulting in a 1-mm-wide gap. Schwann cell migration within the gap was monitored microscopically at given time intervals and was quantified using an image analysis system. The extent of cell proliferation was estimated by BrdU incorporation, and cell migration was quantified both in the absence and presence of cytosine arabinoside. We found that, in the absence of serum, beta-neuregulin at a dose submaximal for proliferation increased the rate of Schwann cell migration by 84%. A more moderate effect was observed when beta-neuregulin was applied in the presence of serum which, however, is by itself responsible for increased Schwann cell motility. To assess the signal transduction pathways involved in this procedure we used one inhibitor of MAPK, PD098059, two inhibitors of PI-3-kinase, wortmannin, and LY0294002, and three different PKC inhibitors. Of these PD098059 inhibited the neuregulin-induced enhancement in Schwann cell migration by 40%, the two PI-3-kinase inhibitors yielded an approximately 20% inhibition while the PKC inhibitors were ineffective. Our data indicate that the action of beta-neuregulin on Schwann cell motility is primarily mediated via the MAPK pathway.