title: DREAM mediates cAMP-dependent, Ca2+-induced stimulation of GFAP gene expression and regulates cortical astrogliogenesis.
abstract: 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-Ca(2+)-DREAM cascade as a new pathway to activate GFAP gene expression during astrocyte differentiation.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Cebolla
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernández-Pérez
authors.forename: Gertrudis
authors.initials: G
authors.lastname: Perea
authors.forename: Alfonso
authors.initials: A
authors.lastname: Araque
authors.forename: Mario
authors.initials: M
authors.lastname: Vallejo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D051605:Kv Channel-Interacting Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C496756:Csen protein, mouse; D005904:Glial Fibrillary Acidic Protein; D051605:Kv Channel-Interacting Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012097:Repressor Proteins; D000242:Cyclic AMP; D002118:Calcium