DREAM Controls the On/Off Switch of Specific Activity-Dependent Transcription Pathways

Abstract

h Changes in nuclear Ca 2؉ homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K ؉ channel interacting protein 3), is a Ca 2؉ -binding protein that binds DNA and represses transcription in a Ca 2؉ -dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca 2؉ -insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activitydependent gene expression programs that control synaptic plasticity, learning, and memory.A major challenge for neuroscience is to identify the regulatory molecules underpinning the storage of information in neurons. Activity-dependent gene expression underlies neuronal plasticity and adaptive responses to different environmental stimuli in the central nervous system (CNS) and is determinant in the formation and storage of memories. Diverse signaling pathways participate in these processes. Among them, changes in intracellular free calcium concentration are the most universal signal, and the final output, in terms of adapted gene expression, is given by a specific set of proteins that decode the calcium signal according to its frequency, subcellular location, and intensity (1-3). A nuclear tool kit of Ca 2ϩ -dependent effectors modifies the activity or the properties of specific transcription factors to regulate gene expression in response to the Ca 2ϩ signal (for reviews, see references 4 and 5). Despite extensive investigation, a detailed mechanistic description of Ca 2ϩ -dependent signaling in the expression of the late, transcription-dependent component of long-term potentiation (LTP) is far from been complete (reviewed in reference 6). Here, we examine the role of the Ca 2ϩ -dependent transcriptional repressor DREAM (downstream regulatory element antagonist modulator) in the control of activity-dependent transcription and the expression of LTP, as well as in learning and memory.The DREAM/calsenilin/KChIP-3 gene belongs to a group of four genes (encoding K ϩ channel interacting proteins 1 to 4 [KChIP-1 to -4]) that regulate the membrane expression and gating of Kv4 potassiu...

Towards a better understanding of cognitive behaviors regulated by gene expression downstream of activity-dependent transcription factors

“…Although the exact details of this pathway are yet to be determined, DREAM might serve as a DG-specific regulator for Ca 2+ signalling to CREB-CBP complex formation. Consistent with this idea, DREAM knockouts show enhanced contextual fear memory (Alexander et al, 2009), and transgenic mice expressing a dominant active DREAM (daDREAM) showed strong deficits in watermaze, a spatial memory task and slight deficit in active avoidance test, all of which involves the hippocampus (Mellstrom et al, 2014). In keeping with evidence that Npas4 and BDNF are regulated by DREAM, daDREAM transgenic mice showed downregulation of GABAergic synapses and enhanced LTP in DG (Mellstrom et al, 2014).…”

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

“…Likewise, the A-type K + channel subunit KChip3 (a member of the NCS-1 like Ca 2+ binding protein family) is known as the transcriptional repressor DREAM (Jo et al 2001;Buxbaum 2004), and can shuttle from the membrane to the nucleus in inverse correlation with cellular Ca 2+ levels (Fig. 1) (Li and Adelman 2000;Sours-Brothers et al 2009;Mellstrom et al 2014).…”

Downstream Regulatory Element Antagonist Modulator (DREAM), a target for anti-thrombotic agents

“…The first EF-hand domain was functionally dead due to the presence of a CPXG motif that prevents Ca 2+ binding (15). Upon an increase in intracellular Ca 2+ , the DREAM tetramer binds Ca 2+ (15, 16), is dissociated from DNA without disruping the tetrameric structure (17), and is exported out of the nucleus to the cytoplasm as dimers, thereby allowing gene transcription (Figure 1) (18). The DRE sequence is observed in multiple genes, including PDYN (prodynorphin), SLC8A3 (Na + -Ca 2+ exchanger), c-fos, HRK , and TNFAIP3 (TNF-α-induced protein 3, A20) (17, 19–22).…”

“…Studies using DREAM KO and Ca 2+ -insensitive/CRE binding(CREB)-independent dominant-active DREAM transgenic mice demonstrated that DREAM is involved in L-DOPA-induced dyskinesias and DREAM decreases L-DOPA-induced expression of FosB, dynorphin-B, and phosphoacetylated histone H3 in the striatum (39). Another study using the same transgenic mice suggested that the expression of dominant-active DREAM in the forebrain results in downregulation of Npas4, thereby reducing GABAergic inhibitory transmission and impairing learning and memory (18). Also, reduced DREAM expression in a transgenic mouse model of Huntington disease results in neuroprotection (40).…”