Abstract
Neurogenesis, which occurs not only in the developing brain but also in restricted regions in the adult brain including the forebrain subventricular zone (SVZ), is regulated by a variety of environmental factors, extracellular signals, and intracellular signal transduction pathways. We investigated whether the cAMP/PKA/cAMP response element(CRE)-binding protein (CREB) signaling pathway is involved in the regulation of cell proliferation of neural stem cells (NSCs) isolated from SVZ of adult mice. Treatment of NSCs with the PKA inhibitor H89 and KT5720 inhibited epidermal growth factor (EGF)-stimulated NSC proliferation. Similar inhibition was also observed when a dominant-negative mutant of CREB was expressed by adenovirus vector infection. EGF treatment increased CRE-mediated transcriptional activity, but this increase was much less than that by treatment with forskolin, an adenylate cyclase activator. Forskolin treatment changed neither basal nor EGF-stimulated proliferation. The PKA inhibitors blocked neither EGF-induced phosphorylation of extracellular signal-regulated kinase (ERK), a protein kinase mediating the EGF mitogenic action, nor nuclear translocation of phosphorylated ERK. These results suggest that basal activity of the cAMP/PKA/CREB pathway is required for the mitogenic signaling of EGF in NSCs at a step downstream of ERK activation. [J Physiol Sci. 2007;57 Suppl:S166]
