Regulation of fosB and ΔfosB mRNA expression: In vivo and in vitro studies

The transcription factor ΔFosB, a truncated splice isoform of FosB, accumulates in brain after several types of chronic stimulation. This accumulation is thought to be mediated by the unique stability of ΔFosB compared to all other Fos family proteins. The goal of the present study was to determine if the relative expression of the two fosB isoforms is also regulated at the mRNA level, thereby further contributing to the selective accumulation of ΔFosB after chronic stimulation. First, unlike the protein, the half-life of ΔfosB mRNA is only slightly longer than that of full-length fosB mRNA both in cultured cells in vitro and in the brain in vivo. Additionally, similar to c-fos, both fosB isoforms are induced abundantly in striatum after acute administration of amphetamine or stress, and partially desensitize after chronic exposures. Surprisingly, the relative ratio of ΔfosB to fosB mRNA increases most significantly after acute, not chronic, stimulation. Finally, overexpression of polypyrimidine tract binding protein (PTB1), which regulates RNA splicing, in cultured cells decreases the relative expression of ΔfosB compared to fosB mRNA. Together, these findings suggest that splicing of fosB pre-mRNA is regulated by the quantity of unspliced transcript available to the splicing machinery. These data provide fundamental information concerning the generation of ΔfosB mRNA, and indicate that the selective accumulation of ΔFosB protein with chronic stimulation does not involve its preferential generation by RNA splicing.