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.

Acute suppression, but not chronic genetic deficiency, of c- fos gene expression impairs long-term memory in aversive taste learning

“…Concerning the cellular processes related to c-fos expression, previous studies have reported finding mutual regulation between c-fos and CREB gene expression (12,43) and involvement of amygdaloid CREB protein synthesis in long-term but not short-term memory of CTA (35). Our data also showed that suppression of Fos synthesis in the AMY by c-fos AS-ODN impaired the long-term retention, but not the acquisition, of CTA.…”

“…The expression of one of the IEGs, c-fos, and the synthesis of the gene product, Fos protein, have been reported to increase in the rat brain in response to various stimuli, including stressful events (6,7) and nonstressful manipulations (8)(9)(10)(11). Fos regulates transcription of other genes as an AP-1 complex and is suggested to contribute to the long-term modifications in neuronal biochemistry and structure proposed to underlie learning (2,12).…”

A systems approach to delineate functions of paralogous transcription factors: Role of the Yap family in the DNA damage response

“…In the future, network states measured under a diverse set of perturbations (both environmental and genetic) will enable further discrimination of the subtle functional differences among family members. The bZIP TF families are also pervasive in higher eukaryotes and are involved in a variety of processes that are critical to the function of the organism, such as embryogenesis, metabolism, and learning and memory (44)(45)(46). An integrative approach offers a powerful means to delineate the even more complicated regulatory networks in these organisms.…”

c-Jun NH2-terminal Kinase (JNK)-interacting Protein-3 (JIP3) Regulates Neuronal Axon Elongation in a Kinesin- and JNK-dependent Manner

“…As a member of the JIPs, JIP3 has been suggested to tether specific JNK signaling modules, thereby promoting signal transmission (3)(4)(5)(6). The JNK pathway is involved in axon formation/polarization, extension, synaptic plasticity, and dendrite development (7)(8)(9)(10)(11). Moreover, as a homology of UNC-16 in Caenorhabditis elegans and Sunday Driver in Drosophila, JIP3 is implicated as an adaptor protein in kinesin-dependent vesicular transport to axons (12,13) and has recently been reported to be a mediator in TrkB anterograde axonal transport in hippocampal neurons (14).…”