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.

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.

Normal CNS myelination in transgenic mice overexpressing MHC class I H-2L(d) in oligodendrocytes.

In demyelinating diseases, such as multiple sclerosis, an upregulation of MHC class I expression is thought to contribute to oligodendrocyte/myelin damage. In order to investigate potential physiological consequences of upregulated MHC class I expression in oligodendrocytes, we generated transgenic mice that overexpress H-2L(d) under the control of the proteolipid protein (PLP) promoter (PLP-L(d) mice). We focused our studies on the MHC class I molecule H-2L(d), because of its unique intracellular transport characteristics. In the CNS of PLP-L(d) mice, H-2L(d) was expressed by oligodendrocytes. Furthermore, H-2L(d) protein was transported to and expressed on the surface of oligodendrocytes. Most importantly, this upregulation of MHC class I expression in the CNS of PLP-L(d) mice did not by itself result in a de- or dysmyelinating phenotype. These transgenic mice are likely to provide a unique and novel tool for the analysis of potential roles of MHC class I-mediated mechanisms in demyelinating pathologies.