Activity-Dependent Transport of the Transcriptional Coactivator CRTC1 from Synapse to Nucleus

Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095-1737, USA.
Cell (Impact Factor: 32.24). 07/2012; 150(1):207-21. DOI: 10.1016/j.cell.2012.05.027
Source: PubMed


Long-lasting changes in synaptic efficacy, such as those underlying long-term memory, require transcription. Activity-dependent transport of synaptically localized transcriptional regulators provides a direct means of coupling synaptic stimulation with changes in transcription. The CREB-regulated transcriptional coactivator (CRTC1), which is required for long-term hippocampal plasticity, binds CREB to potently promote transcription. We show that CRTC1 localizes to synapses in silenced hippocampal neurons but translocates to the nucleus in response to localized synaptic stimulation. Regulated nuclear translocation occurs only in excitatory neurons and requires calcium influx and calcineurin activation. CRTC1 is controlled in a dual fashion with activity regulating CRTC1 nuclear translocation and cAMP modulating its persistence in the nucleus. Neuronal activity triggers a complex change in CRTC1 phosphorylation, suggesting that CRTC1 may link specific types of stimuli to specific changes in gene expression. Together, our results indicate that synapse-to-nuclear transport of CRTC1 dynamically informs the nucleus about synaptic activity.

Download full-text


Available from: Kelsey C Martin, Sep 04, 2015
41 Reads
  • Source
    • "For example, representative proteins from the CA1 region include many that are known to be involved in synaptic plasticity and long-term potentiation (LTP), including: CREB-regulated transcription coactivator 1 (CRTC1), protein kinase C zeta type (PRKCZ), NMDA receptor synaptonuclear signaling, neuronal migration factor (NSMF), and RNA-binding protein 4 (RBM4). CRTC1 is involved in late-phase LTP (L-LTP) maintenance at the Schaffer collateral–CA1 synapses in the hippocampus [27]. PRKCZ is necessary and sufficient for LTP maintenance in CA1 pyramidal cells [28]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The hippocampus is one of the most essential components of the human brain and plays an important role in learning and memory. The hippocampus has drawn great attention from scientists and clinicians due to its clinical importance in diseases such as Alzheimer's disease (AD), non-AD dementia, and epilepsy.. Understanding the function of the hippocampus and related disease mechanisms requires comprehensive knowledge of the orchestration of the genome, epigenome, transcriptome, proteome, and post-translational modifications (PTMs) of proteins. The past decade has seen remarkable advances in the high-throughput sequencing techniques that are collectively called next generation sequencing (NGS). NGS enables the precise analysis of gene expression profiles in cells and tissues, allowing powerful and more feasible integration of expression data from the gene level to the protein level, even allowing "-omic" level assessment of PTMs. In addition, improved bioinformatics algorithms coupled with NGS technology are finally opening a new era for scientists to discover previously unidentified and elusive proteins. In the present review, we will focus mainly on the proteomics of the human hippocampus with an emphasis on the integrated analysis of genomics, epigenomics, transcriptomics, and proteomics. Finally, we will discuss our perspectives on the potential and future of proteomics in the field of hippocampal biology. This article is part of a Special Issue entitled: Neuroproteomics: Applications in Neuroscience and Neurology. Copyright © 2015 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics 03/2015; 1854(7). DOI:10.1016/j.bbapap.2015.02.010 · 2.75 Impact Factor
  • Source
    • "Another interesting data observed in this report is that only treatment with bicuculline, but not NMDA, significantly increased the expression of Grin2b right after 6 h stimulation. Bicuculline administration blocks the inhibitory effect of GABAA receptors, one of major receptors existed in interneurons, and indirectly promotes excitatory synaptic transmission mediated mainly by glutamatergic neurotransmission (Ferraro et al., 1999; Ch’ng et al., 2012). All of ionotropic glutamate receptors (NMDAR, AMPAR, and kainate receptors), metabotropic glutamate receptors and voltage-gated calcium channels can be indirectly activated by bicuculline and lead to calcium influx (Niciu et al., 2012; Banerjee et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The activity-regulated gene expression of transcription factors is required for neural plasticity and function in response to neuronal stimulation. T-brain-1 (TBR1), a critical neuron-specific transcription factor for forebrain development, has been recognized as a high-confidence risk gene for autism spectrum disorders (ASDs). Here, we show that in addition to its role in brain development, Tbr1 responds to neuronal activation and further modulates the Grin2b expression in adult brains and mature neurons. The expression levels of Tbr1 were investigated using both immunostaining and quantitative RT-PCR analyses. We found that the mRNA and protein expression levels of Tbr1 are induced by excitatory synaptic transmission driven by bicuculline or glutamate treatment in cultured mature neurons. The upregulation of Tbr1 expression requires the activation of both AMPA and NMDA receptors. Furthermore, behavioral training triggers Tbr1 induction in the adult mouse brain. The elevation of Tbr1 expression is associated with Grin2b upregulation in both mature neurons and adult brains. Using Tbr1-deficient neurons, we further demonstrated that TBR1 is required for the induction of Grin2b upon neuronal activation. Taken together with the previous studies showing that TBR1 binds the Grin2b promoter and controls expression of luciferase reporter driven by Grin2b promoter, the evidence suggests that TBR1 directly controls Grin2b expression in mature neurons. We also found that the addition of the calcium-calmodulin kinase II (CaMKII) antagonist KN-93, but not the calcium-dependent phosphatase calcineurin antagonist cyclosporin A, to cultured mature neurons noticeably inhibited Tbr1 induction, indicating that neuronal activation upregulates Tbr1 expression in a CaMKII-dependent manner. In conclusion, our study suggests that Tbr1 plays an important role in adult mouse brains in response to neuronal activation to modulate the activity-regulated gene transcription required for neural p
    Frontiers in Cellular Neuroscience 09/2014; 8:280. DOI:10.3389/fncel.2014.00280 · 4.29 Impact Factor
  • Source
    • "PKA and PP2B mediate synergistic effect on TORC1 dependent transcription by decreasing the level of phosphorylated TORC1 and increasing the level of unphosphorylated TORC1 in the nucleus. The nuclear TORC1 binds to the CREB and upregulates CRE-dependent transcription [64] (Fig. 3F). This sub model was parameterized as a part of the composite model by using published experiments, as follows. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Synaptic plasticity requires transcription and translation to establish long-term changes that form the basis for long term memory. Diverse stimuli, such as synaptic activity and growth factors, trigger synthesis of mRNA to regulate changes at the synapse. The palette of possible mRNAs is vast, and a key question is how the cell selects which mRNAs to synthesize. To address this molecular decision-making, we have developed a biochemically detailed model of synaptic-activity triggered mRNA synthesis. We find that there are distinct time-courses and amplitudes of different branches of the mRNA regulatory signaling pathways, which carry out pattern-selective combinatorial decoding of stimulus patterns into distinct mRNA subtypes. Distinct, simultaneously arriving input patterns that impinge on the transcriptional control network interact nonlinearly to generate novel mRNA combinations. Our model combines major regulatory pathways and their interactions connecting synaptic input to mRNA synthesis. We parameterized and validated the model by incorporating data from multiple published experiments. The model replicates outcomes of knockout experiments. We suggest that the pattern-selectivity mechanisms analyzed in this model may act in many cell types to confer the capability to decode temporal patterns into combinatorial mRNA expression.
    PLoS ONE 05/2014; 9(5):e95154. DOI:10.1371/journal.pone.0095154 · 3.23 Impact Factor
Show more