title: AP-1 functions upstream of CREB to control synaptic plasticity in Drosophila.
abstract: Activity-regulated gene expression mediates many aspects of neural plasticity, including long-term memory. In the prevailing view, patterned synaptic activity causes kinase-mediated activation of the transcription factor cyclic AMP response-element-binding protein, CREB. Together with appropriate cofactors, CREB then transcriptionally induces a group of 'immediate early' transcription factors and, eventually, effector proteins that establish or consolidate synaptic change. Here, using a Drosophila model synapse, we analyse cellular functions and regulation of the best known immediate early transcription factor, AP-1; a heterodimer of the basic leucine zipper proteins Fos and Jun. We observe that AP-1 positively regulates both synaptic strength and synapse number, thus showing a greater range of influence than CREB. Observations from genetic epistasis and RNA quantification experiments indicate that AP-1 acts upstream of CREB, regulates levels of CREB messenger RNA, and functions at the top of the hierarchy of transcription factors known to regulate long-term plasticity. A Jun-kinase signalling module provides a CREB-independent route for neuronal AP-1 activation; thus, CREB regulation of AP-1 expression may, in some neurons, constitute a positive feedback loop rather than the primary step in AP-1 activation.
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson 85721, USA.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Sanyal
authors.forename: David J
authors.initials: DJ
authors.lastname: Sandstrom
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hoeffer
authors.forename: Mani
authors.initials: M
authors.lastname: Ramaswami
mesh_terms: D000818:Animals; D002452:Cell Count; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019281:Dimerization; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D004594:Electrophysiology; D004843:Epistasis, Genetic; D018507:Gene Expression Regulation, Developmental; D048031:JNK Mitogen-Activated Protein Kinases; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009469:Neuromuscular Junction / Q000166:cytology / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism; D009473:Neuronal Plasticity; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000201:enzymology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D000242:Cyclic AMP; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases