Effect of cyclic AMP on the expression of myelin basic protein species and myelin proteolipid protein in committed oligodendrocytes: Differential involvement of the transcription factor CREB

Abstract

Our previous results support the idea that CREB (cyclic AMP-response element binding protein) may be a mediator of neuroligand and growth factor signals that, coupled to different signal transduction pathways, play different roles at specific stages of oligodendrocyte development. In the early stages, when cells are immature precursors, CREB may play a role as a mediator of protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) pathways regulating cell proliferation. In contrast, at a later stage, when cells are already committed oligodendrocytes, CREB seems to play an important role as a mediator in the stimulation of myelin basic protein (MBP) expression by cyclic AMP (cAMP). In this study, we have investigated whether cAMP and CREB play a role in regulating the expression of all or on the other hand particular MBP isoforms. The results indicated that treatment of committed oligodendrocytes with the cAMP analogue db-cAMP results in a pattern of expression of MBP-related polypeptides that most closely resembles the pattern of MBPs observed in cerebra from adult animals. Experiments in which CREB expression was inhibited using a CREB antisense oligonucleotide, suggested that CREB is involved in the cAMP-dependent stimulation of all the MBP isoforms. In contrast, we have found that db-cAMP stimulates the expression of myelin proteolipid protein (PLP) in a process that occurs despite inhibition of CREB expression. These results support the idea that cAMP stimulates the maturation of oligodendrocytes and stress the fact multiple mechanisms may convey the action of this second messenger modulating oligodendrocyte differentiation and myelination.

A Novel Nuclear Signaling Pathway for Thromboxane A2 Receptors in Oligodendrocytes: Evidence for Signaling Compartmentalization during Differentiation

“…It was found that stimulation of the nuclear TPR pool caused an elevation in nuclear cAMP levels. Furthermore, this elevated cAMP was found to activate CREB, which is known to promote OLG survival (20,42) and stimulate MBP expression (1,43). The direct association of TPRs with MBP expression was confirmed in subsequent experiments, revealing nuclear TPR-mediated increases in MBP mRNA levels.…”

The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules

“…Treatments that induce a sustained elevation of cAMP levels in oligodendrocytes activate CREB and subsequently increase MBP protein levels by activating the MBP promoter (24,26,27,44). Conversely, inactivation of CREB has been reported in the presence of inhibitors of oligodendrocyte maturation, such as GSK3␤ (45) or CNS myelin (12).…”

“…One of the best characterized PKA-activated transcription factors is CREB, which is known to stimulate MBP expression in oligodendrocytes (24,26,27). To examine whether activation of CREB in rat differentiating oligodendrocytes is altered upon GPR17 stimulation, we measured CREB phosphorylation in the presence of MDL29,951.…”

Apotransferrin promotes the differentiation of two oligodendroglial cell lines

“…Several studies have shown that OLG differentiation is stimulated by cAMP (McMorris, 1983;Pleasure et al, 1986;McMorris, 1989, 1990) and elevated levels of the transcription factor CREB, which mediates cAMP-dependent stimulation of MBP expression and the outgrowth of OLGc processes (Sato-Bigbee et al, 1994Sato-Bigbee and De Vries, 1996;Afshari et al, 2001). Skorupa and McMorris (1995) reported that in OLGcs cultured during 1-8 days in vitro, increased cAMP levels upregulated MBP and PLP genes, whereas after 8 days in vitro, these genes were downregulated, suggesting that the effect of cAMP on OLGcs depends on the maturation of the cells.…”