Defense Date


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Degree Name

Master of Science



First Advisor

Carmen Sato-Bigbee


In the central nervous system (CNS), oligodendrocytes (OLGs) are the cells responsible for producing the myelin membrane which allows for the saltatory conduction of neuronal impulses. We have previously shown that CREB (cAMP response element binding protein), a transcription factor that belongs to a large family bZip (basic leucine zipper) proteins, could be a mediator of neuronal signals that, coupled to different signal transduction pathways, may play different regulatory roles at specific stages of oligodendrocyte development. We have found before that, in committed OLGs, CREB activation by phosphorylation can be triggered by β-adrenergic stimulation and appears to play a role in the induction of OLG differentiation by cAMP. In contrast, in 01.0 precursor cells, CREB phosphorylation is stimulated by neuroligands that increase calcium levels by a process that involves a mitogen activated protein kinase (MAPK)/protein kinase C (PKC) pathway. This observation suggested that, at this early developmental stage, CREB could play a role in regulating cell proliferation In support Of this hypothesis, we have now found that a rapid and dramatic stimulation of CREB phosphorylation is one ofthe earliest events that precedes the increase in cell proliferation that is observed when OLG precursors are treated with neurotrophin-3 (NT-3) Moreover, our present results also showed that down-regulation of CREB expression in the OLG precursors abolished the increase in cell proliferation that is observed when the cultures are treated with NT-3. Experiments in which CREB phosphorylation was investigated in the presence of different kinase inhibitors indicated that the activation of this transcription factor in the presence of NT-3 is mediated by the concerted action of MAPK- and PKC-dependent signal transduction pathways. Additional experiments using specific inhibitors of protein kinase A (PKA), Caz2+-calmodulin-dependent kinase (CamK) and phosphatidylinositol 3-kinase (PI3K) pathways suggested that these kinases may not play a significant role in mediating CREB phosphorylation by NT-3. However, further studies are required for more conclusive results about these kinases. Thus, our present results support the idea that stimulation of OLG proliferation by NT-3 involves the CREB transcription factor and its activation by MAPK- and PKC-dependent signal transduction pathways.


Scanned, with permission from the author, from the original print version, which resides in University Archives.


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