Interaction of fibroblast growth factor 2 (FGF2) and notch signaling components in inhibition of oligodendrocyte progenitor (OP) differentiation

Abstract

Oligodendrocyte progenitor (OP) cell differentiation is a critical process of developmental myelination, tumor formation, and remyelination in the CNS. Activation of the fibroblast growth factor 2 (FGF2) or notch pathway can inhibit differentiation of OP cells. The current study examines the interaction of FGF2 and notch signaling components in regulating OP differentiation. Cultured neonatal rat brain OP cells were used for transfection-based promoter assays and for infection with retroviruses expressing a GFP reporter to monitor OP differentiation into oligodendrocytes or astrocytes. FGF2 treatment resulted in a four-fold increase of transcriptional activity from the promoter region of Hes5, a notch pathway target gene. FGF2 inhibition of OP differentiation into oligodendrocytes was perturbed by retroviral expression of a dominant negative construct for mastermind-like 1, which is an important co-activator of transcription for notch target genes. OP differentiation into oligodendrocytes was reduced by co-culture with fibroblasts expressing Jagged1, a ligand for notch receptors. This Jagged1 inhibition of OP differentiation was not altered by retroviral expression of a dominant negative FGF receptor construct. Constitutive activation of notch signaling, by retroviral expression of the Notch1 intracellular domain, greatly reduced OP differentiation into either oligodendrocytes or astrocytes and did not require FGF2 signaling. These findings indicate that inhibition of OP differentiation through the Notch1 pathway was not influenced by FGF2 signaling. However, FGF2 signaling may interact with down stream components of the notch signaling pathway, including mastermind-like1 and Hes5, to inhibit OP differentiation into oligodendrocytes.