ASTROCYTE GROWTH IS REGULATED BY NEUROPEPTIDES THROUGH TIS-8 AND BASIC FIBROBLAST GROWTH-FACTOR

The important intracellular mechanisms of astrocyte growth are not wel l defined. Using an inhibitor of astrocyte proliferation, atrial natri uretic peptide (ANP), and the glial mitogen endothelin (ET-3), we soug ht a common pathway for growth regulation in these neural cells. In cu ltured fetal rat diencephalic astrocytes, ANP selectively and rapidly inhibited the Tis 8 immediate early gene and protein. After 4 h, ANP s electively inhibited the basic fibroblast growth factor (bFGF) gene an d protein. ET-3 significantly stimulated both Tis 8 and bFGF mRNAs and protein, but also stimulated several other immediate early and growth factor/receptor genes. An antisense oligonucleotide to Tis 8 strongly prevented ET-stimulated thymidine incorporation, while the inhibitory action of ANP was enhanced. The Tis 8 antisense oligonucleotide also significantly reversed ET-stimulated bFGF transcription and enhanced t he bFGF inhibition caused hy ANP. In addition, an antisense oligonucle otide to bFGF significantly reversed the ET-stimulated thymidine incor poration and enhanced the ANP inhibition of DNA synthesis. The sequent ial modulation of Tis 8, followed by bFGF, provides a novel mechanism for both positive and negative regulation of astrocyte growth by endog enous neuropeptides.