title: Activity-Independent Effects of CREB on Neuronal Survival and Differentiation during Mouse Cerebral Cortex Development.
abstract: Neuronal survival and morphological maturation depends on the action of the transcription factor calcium responsive element binding protein (CREB), which regulates expression of several target genes in an activity-dependent manner. However, it remains largely unknown whether CREB-mediated transcription could play a role at early stages of neuronal differentiation, prior to the establishment of functional synaptic contacts. Here, we show that CREB is phosphorylated at very early stages of neuronal differentiation in vivo and in vitro, even in the absence of depolarizing agents. Using genetic tools, we also show that inhibition of CREB-signaling affects neuronal growth and survival in vitro without affecting cell proliferation and neurogenesis. Expression of A-CREB or M-CREB, 2 dominant-negative inhibitors of CREB, decreases cell survival and the complexity of neuronal arborization. Similar changes are observed in neurons treated with protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitors, which also show decreased levels of pCREBSer133. Notably, expression of CREB-FY, a Tyr134Phe CREB mutant with a lower Km for phosphorylation, partly rescues the effects of PKA and CaMKII inhibition. Our data indicate that CREB-mediated signaling play important roles at early stages of cortical neuron differentiation, prior to the establishment of fully functional synaptic contacts.
authors.affiliation: Brain Institute, Federal University of Rio Grande do Norte, Natal 59056-450, Brazil.
authors.forename: Bruna Soares
authors.initials: BS
authors.lastname: Landeira
authors.affiliation: Brain Institute, Federal University of Rio Grande do Norte, Natal 59056-450, Brazil.
authors.forename: Themis Taynah da Silva
authors.initials: TTDS
authors.lastname: Santana
authors.affiliation: Brain Institute, Federal University of Rio Grande do Norte, Natal 59056-450, Brazil.
authors.forename: Jéssica Alves de Medeiros
authors.initials: JAM
authors.lastname: Araújo
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Elie I
authors.initials: EI
authors.lastname: Tabet
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstr. 26, 4058 Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: Brain Institute, Federal University of Rio Grande do Norte, Natal 59056-450, Brazil.
authors.forename: Marcos R
authors.initials: MR
authors.lastname: Costa
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D047428:Protein Kinase Inhibitors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CREB signaling; cortex; dendritic differentiation; immature neurons; neuronal survival