Different neuroligands and signal transduction pathways stimulate CREB phosphorylation at specific developmental stages along oligodendrocyte differentiation

We have shown previously that the pattern of expression of the transcriptio n factor CREB (cyclic AMP-response element binding protein) in developing o ligodendrocytes (OLGs) suggests a role during a period that precedes the pe ak of myelination in rat brain. We have now investigated the signaling path ways that could be responsible for activating CREB by phosphorylation at di fferent stages along OLG maturation, CREB phosphorylation was studied in sh ort-term cultures of immature OLG precursor cells and young OLGs isolated f rom 4- and 11-day-old rat cerebrum, respectively. The results indicated tha t at both developmental stages, CREB phosphorylation could be stimulated by either increased concentrations of cyclic AMP and cyclic AMP-dependent pro tein kinase activation or increased Ca2+ levels and a protein kinase C acti vity. The results also showed that CREB phosphorylation in immature OLG pre cursor cells could be up-regulated by treatment with histamine, carbachol, glutamate, and ATP (neuroligands known to increase Ca2+ levels in these cel ls), by signaling cascade(s) that involve a protein kinase C activity, as w ell as the mitogen-activated protein kinase pathway. In contrast, in cells isolated from 11-day-old rats, at a developmental stage that immediately pr ecedes the beginning of the active period of myelin synthesis, CREB phospho rylation was only stimulated by treatment with the beta-adrenergic agonist isoproterenol in a process that appears to be mediated by a cyclic AMP/cycl ic AMP-dependent protein kinase-dependent pathway. These results support th e idea that CREB could be a mediator of neuronal signals that, coupled to s pecific signal transduction cascades, may play different regulatory roles a t specific stages along OLG differentiation.