Schwann cells proliferate, migrate, and act as sources of neurotrophic support during development and regeneration of peripheral nerves. Recent studies have demonstrated that neuregulins, a family of growth factors secreted by developing motor and peripheral neurons, influence Schwann cell development. In this study, we use three distinct assays to show that glial growth factor 2 (GGF2), a secreted neuregulin, exerts multiple effects on mature Schwann cells in vitro. At doses submaximal for proliferation, GGF2 increases the motility of Schwann cells cultured on peripheral nerve cryosections. Furthermore, in a novel bioassay, focal application of GGF2 causes directed migration in conventional monolayer cultures of directed migration of Schwann cells. At higher doses, GGF2 causes proliferation, as described previously. In a new explant culture system designed to emulate entubulation repair of transected peripheral nerves, GGF2 concentrations greater than necessary to saturate the mitotic response induce the secretion by Schwann cells of activities that promote sympathetic neuron survival and outgrowth. These findings support a model in which neuregulins secreted by peripheral neurons are key components of reciprocal neuron-glia interactions that are important for peripheral nerve development and regeneration.

Neuregulins (NRGs) are expressed in spinal cord motor neurons and accumulate at the neuromuscular junction where they may increase the synthesis of postsynaptic acetylcholine receptors and voltage-gated sodium channels. We demonstrate here that NRG expression is selectively increased in rat ventral spinal cord neurons at approximately the time that nerve-muscle synapses first form. A rapid increase in NRG mRNA and protein expression was induced in vitro in cultured rat spinal motor neurons by brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, or glial-cell-line-derived neurotrophic factor. Agrin expression was not affected by these factors over the same time course. Brain-derived neurotrophic factor, but not neurotrophin-3, selectively regulated immunoglobulin domain-containing splice variants of NRG, which are likely to be important for binding to the synaptic basal lamina. Regulation of NRG expression in motor neurons by muscle-derived neurotrophic factors may represent one portion of a reciprocal, regulatory loop that promotes neuromuscular synapse development.