GLIAL GROWTH-FACTORS I-III ARE SPECIFIC MITOGENS FOR GLIAL-CELLS

Recently we identified three novel Schwann cell mitogens named GGF (gl ial growth factor)-I. (34 kDa), GGF-II (59 kDa), and GGF-III (45 kDa), and provided evidence that they are three distinct but structurally r elated members of a larger family of factors, which includes heregulin , neu differentiation factor, and acetylcholine receptor-inducing acti vity (ARIA). We report here the characterization of the mitogenic and trophic activities for all three forms of GGF on rat Schwann cells and several other cell types. GGF-I, GGF-II, and GGF-III are potent mitog ens for rat Schwann cells in vitro at nanomolar concentrations, wherea s at lower concentrations they promote Schwann cell survival, in the a bsence of cAMP elevating agents. Forskolin, an adenylate cyclase activ ator, potently synergizes with the GGFs by an indirect mechanism, poss ibly involving transcriptional activation of GGF receptor(s). In addit ion, the GGFs stimulate DNA synthesis in rat glioma C6 cells, and in S K-BR-3 cells, which overexpress the p185 neu/erbB2. Fibroblasts obtain ed from different sources are weakly stimulated by GGFs, whereas PC12 cells are unable to respond under a variety of experimental conditions . These observations are consistent with the proposal that GGF-I, GGF- II, and GGF-III are a set of potent glial cell mitogens and putative l igands of members of the EGF receptor family, namely p185 neu/erbB2, p 160/erbB3, and p180/erbB4, which may play important roles in the devel opment, regeneration, and tumor biology of the peripheral nervous syst em. (C) 1996 Wiley-Liss, Inc.