Possible role of CREB in the stimulation of oligodendrocyte precursor cellproliferation by neurotrophin-3

We have previously shown that the transcription factor CREB (cyclic AMP-res ponse element binding protein) could be a mediator of neuronal signals that , coupled to different signal transduction pathways, may play different reg ulatory roles at specific stages of oligodendrocyte (OLG) development. We h ave found before that in committed OLGs, CREB activation by phosphorylation can be triggered by beta-adrenergic stimulation and appears to play a role in the induction of OLG differentiation by cyclic AMP. In contrast, in OLG precursor cells, CREB phosphorylation is stimulated by neuroligands that i ncrease calcium levels by a process that involves a mitogen-activated prote in kinase (MAPK)/protein kinase C (PKC) pathway. This observation suggested that at this early developmental stage, CREB could play a role in regulati ng cell proliferation. In support of this hypothesis, we have now found tha t a rapid and dramatic stimulation of CREB phosphorylation is one of the ea rliest events that precedes the increase in cell proliferation that is obse rved when OLG precursors are treated with neurotrophin-3 (NT-3), Experiment s in which CREB phosphorylation was investigated in the presence of differe nt kinase inhibitors indicated that the activation of this transcription fa ctor in the presence of NT-3 is mediated by the concerted action of MAPK- a nd PKC-dependent signal transduction pathways. Moreover, our present result s also showed that down-regulation of CREB expression in the OLG precursors abolished the increase in DNA synthesis that is observed when the cultures are treated with NT-3. Thus, these results support the idea that in immatu re OLG precursors, CREB plays an important role in transducing signals whic h, like NT-3, may regulate cell proliferation.