Post-transcriptional regulation of PDGFα-receptor in O-2A progenitor cells

Platelet-derived growth factor alpha-receptor (PDGF alpha R) mediated signaling plays a key role in the development of glial cells of the central nervous system. In vivo and in vitro studies show that PDGF alpha R is actively expressed in proliferative and motile oligodendrocyte type-2 astrocyte (O-2A) glial progenitor cells. However, PDGF alpha R expression is barely detectable in mature glial cells. The exact mechanism underlying the loss of PDGF alpha R expression is unknown. In this study, we employed a rat brain-derived O-2A glial progenitor cell line, CG4 as a culture model to investigate signals capable of inhibiting PDGF alpha R gene expression. PDGF alpha R mRNA levels decreased significantly as CG4 cells differentiated into both oligodendrocyte and astrocyte lineages. We showed that inhibition of PDGF alpha R expression was promoted by prostaglandin E2 via protein kinase A activation. Both cAMP analogs (db-cAMP and 8'bromo-cAMP) and adenylate cyclase activator (forskolin) were potent suppressors of PDGF alpha R expression in CG4 cells. This inhibitory effect resulted from an increased destabilization of PDGF alpha R mRNA instead of a decreased PDGF alpha R gene transcription. Importantly, db-cAMP failed to reduce PDGF alpha R mRNA levels in several PDGF alpha R over-expressing human glioma cell lines. Together, these results suggest that cAMP-dependent pathway played a key regulatory role in controlling PDGF alpha R mRNA levels during normal glial development, and that a breakdown in the cross talk between cAMP and PDGF pathways may underlie the uncontrolled proliferation and immature differentiation state in the glial tumors.