REGULATION OF ASTROCYTE GFAP EXPRESSION BY TGF-BETA-1 AND FGF-2

Astrocytes play a critical role in the development of the CNS and its response to injury and disease. A key indicator of astrocyte activatio n is the increased accumulation of intermediate filaments composed of glial fibrillary acidic protein (GFAP). Treatment of astrocytes in vit ro with transforming growth factor-beta 1 (TGF-beta 1) produced little morphological change, but resulted in a significant increase in GFAP mRNA and protein. Treatment with basic fibroblast growth factor (FGF-2 ) produced a dramatic change from a polygonal to a stellate morphology , and resulted in a significant decrease in GFAP mRNA and protein. FGF -S also inhibited the TGF-beta 1-mediated increase in GFAP mRNA and pr otein. Cycloheximide did not block the effects of TOE-beta 1 or FGF-2 on GFAP mRNA levels, but blocked the inhibitory effects of FGF-2 on th e TGF-beta 1-mediated increase in GFAP expression. All effects of FGF- 2 were blocked by co-incubation with 5'-methylthioadenosine, a specifi c inhibitor of FGF-2-induced tyrosine kinase activity and FGF receptor (FGFR) autophosphorylation. We also examined astrocyte expression of FGFR, and demonstrate the presence of FGFR 1 and 2, and lower levels o f FGFR 3. Our results demonstrate that TGF-beta 1 and FGF-2 cause diff erential effects on the astrocyte cytoskeleton and morphology, suggest ing an uncoupling of process outgrowth from GFAP synthesis. (C) 1998 W iley-Liss, Inc.