Beatriz Cebolla, Antonio Fernández-Pérez, Gertrudis Perea, Alfonso Araque, and Mario Vallejo
The Journal of Neuroscience, June 25, 2008, 28(26):6703-6713; doi:10.1523/JNEUROSCI.0215-08.2008
In the developing mouse brain, once the generation of neurons is mostly completed during the prenatal period, precisely coordinated signals act on competent neural precursors to direct their differentiation into astrocytes, which occurs mostly after birth. Among these signals, those provided by neurotrophic cytokines and bone morphogenetic proteins appear to have a key role in triggering the neurogenic to gliogenic switch and in regulating astrocyte numbers. In addition, we have reported previously that the neurotrophic peptide pituitary adenylate cyclase-activating polypeptide (PACAP) is able to promote astrocyte differentiation of cortical precursors via activation of a cAMP-dependent pathway. Signals acting on progenitor cells of the developing cortex to generate astrocytes activate glial fibrillary acidic protein (GFAP) gene expression, but the transcriptional mechanisms that regulate this activation are unclear. Here, we identify the previously known transcriptional repressor downstream regulatory element antagonist modulator (DREAM) as an activator of GFAP gene expression. We found that DREAM occupies specific sites on the GFAP promoter before and after differentiation is initiated by exposure of cortical progenitor cells to PACAP. PACAP raises intracellular calcium concentration via a mechanism that requires cAMP, and DREAM-mediated transactivation of the GFAP gene requires the integrity of calcium-binding domains. Cortical progenitor cells from dream–/– mice fail to express GFAP in response to PACAP. Moreover, the neonatal cortex of dream–/– mice exhibits a reduced number of astrocytes and increased number of neurons. These results identify the PACAP-cAMP-Ca2+-DREAM cascade as a new pathway to activate GFAP gene expression during astrocyte differentiation.