REGULATION OF RAT SCHWANN-CELL P-O EXPRESSION AND DNA-SYNTHESIS BY INSULIN-LIKE GROWTH-FACTORS IN-VITRO

Myelination by Schwann cells is likely to be regulated in vivo by posi tive and negative epigenetic factors. In Vitro, the positive regulatio n of myelin differentiation, in particular expression of the major mye lin protein P-0, can be mimicked by cAMP elevating agents, while serum , transforming growth factor (TGF)beta s, and fibroblast growth factor (FGF)2 have been shown to exert a negative effect on this differentia tion. Growth factors which promote P-0 induction have not, however, be en identified previously. Using a forskolin concentration (0.4 mu M) w hich alone produces little P-0 mRNA or protein induction, we show that insulin-like growth factor (IGF)-I, IGF-II and high concentrations of insulin promote high levels of P-0 induction, although in the absence of forskolin they have no effect. Another event related to Schwann ce ll differentiation, induction of galactocerebroside expression in resp onse to cAMP analogues, is also potentiated by IGFs. In a different co ntext, IGFs regulate Schwann cell DNA synthesis. We find that in defin ed medium forskolin plus FGF2, TGF beta or platelet-derived growth fac tor (PDGF) BE causes minimal DNA synthesis in the absence of IGFs and that IGFs act as potent mitogens under these conditions. IGFs also pot entiate DNA synthesis induced by beta isoforms of neu-differentiation factors (NDFs), although in this case considerable DNA synthesis occur s even in the absence of IGF. These results show that IGFs can act as powerful stimulators of both proliferation and differentiation in Schw ann cells, and that the total growth factor input determines which of these pathways IGFs will promote.