Signalling pathways linking proliferation and survival in oligodendrocyte progenitors

Our previous results support the idea that the transcription factor CREB mediates the action of neuroligand and growth factor signals that coupled to different signalling pathways, play different roles at specific stages of oligodendrocyte (OLG) development. We have found before that the stimulation of OLG progenitor cell proliferation by neurotrophin-3 (NT-3) is preceded by a dramatic increase in CREB phosphorylation by both MAPK and PKC signalling pathways. In addition, we showed that inhibition of CREB expression abolished the NT-3 dependent stimulation of OLG proliferation. We have now found that treatment of OLG progenitors with NT-3 also stimulates the expression of the antiapoptotic protein bcl-2. Interestingly, the bcl-2 gene promoter contains a CREB binding site and thus, this transcription factor may also be involved in modulating the survival of OLG progenitors. In support of this hypothesis, we found that the NT-3 dependent stimulation of bcl-2 expression is dramatically decreased when CREB levels in the cells are down regulated by treatment with CREB antisense oligonucleotide. The role of CREB in regulating bcl-2 expression in the OLG progenitors is further supported by transient transfection experiments using a luciferase reporter gene driven by the promoter region of the bcl-2 gene. The experiments indicated that the activity of the bcl-2 promoter was significantly enhanced by incubating the cells with NT-3. However, this response was abolished by mutations in the promoter at the CREB binding site. Altogether, these results support the idea that signalling pathways targeting CREB may play an important role in linking cell proliferation and survival of OLG progenitors.