Retrograde Transport of Transcription Factor NF-κB in Living Neurons

Wellmann, Henning; Kaltschmidt, Barbara; Kaltschmidt, Christian

doi:10.1074/jbc.m009253200

Cited by 105 publications

(60 citation statements)

References 54 publications

(82 reference statements)

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“…NF-B was the first transcription factor to be localized to synaptic regions in the CNS (Korner et al, 1989). Several subsequent studies have confirmed that latent NF-B dimers are present in synaptic regions, and that once activated, NF-B translocates from the synapse to the nucleus (Kaltschmidt et al, 1993(Kaltschmidt et al, , 1995Meberg et al, 1996;Cruise et al, 2000;Wellmann et al, 2001;Meffert et al, 2003;Scholzke et al, 2003). This suggests that the NF-B transcription factor family may act as a synapse-to-nucleus messenger in the nervous system.…”

Section: Discussionmentioning

confidence: 89%

Regulation of Nuclear Factor κB in the Hippocampus by Group I Metabotropic Glutamate Receptors

O’Riordan¹,

Huang²,

Pizzi³

et al. 2006

J. Neurosci.

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Section: Discussionmentioning

confidence: 89%

Regulation of Nuclear Factor κB in the Hippocampus by Group I Metabotropic Glutamate Receptors

O’Riordan¹,

Huang²,

Pizzi³

et al. 2006

J. Neurosci.

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“…Stimulus-induced nuclear import of transcription factors provides a potentially more direct means of signaling from sites of stimulation to the nucleus (30,31). A number of transcription factors and transcriptional regulators, including NF B, Elk-1, NFAT, and CAMAP have indeed been shown to translocate from distal processes to the nucleus in neurons (32)(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons

Lai¹,

Zhao²,

Ch’ng³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

101

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Signals received at distal synapses of neurons must be conveyed to the nucleus to initiate the changes in transcription that underlie long-lasting synaptic plasticity. The presence of importin nuclear transporters and of select transcription factors at synapses raises the possibility that importins directly transport transcription factors from synapse to nucleus to modulate gene expression. Here, we show that cyclic AMP response element binding protein 2 (CREB2)/activating transcription factor 4 (ATF4), a transcriptional repressor that modulates long-term synaptic plasticity and memory, localizes to distal dendrites of rodent hippocampal neurons and neurites of Aplysia sensory neurons (SNs) and binds to specific importin ␣ isoforms. Binding of CREB2 to importin ␣ is required for its transport from distal dendrites to the soma and for its translocation into the nucleus. CREB2 accumulates in the nucleus during long-term depression (LTD) but not long-term potentiation of rodent hippocampal synapses, and during LTD but not long-term facilitation (LTF) of Aplysia sensory-motor synapses. Time-lapse microscopy of CREB2 tagged with a photoconvertible fluorescent protein further reveals retrograde transport of CREB2 from distal neurites to the nucleus of Aplysia SN during phenylalaninemethionine-arginine-phenylalanine-amide (FMRFamide)-induced LTD. Together, our findings indicate that CREB2 is a novel cargo of importin ␣ that translocates from distal synaptic sites to the nucleus after stimuli that induce LTD of neuronal synapses.Aplysia ͉ hippocampus ͉ transcription ͉ long-term depression ͉ dendra S ynaptic plasticity is critical to cognition and memory formation. Long-lasting forms of synaptic plasticity require both transcription and translation (1-3), and specific patterns and strengths of synaptic stimulation trigger changes in neuronal gene expression (4). However, relatively little is known about how signals are transported from synapse to nucleus to regulate transcription. Many types of synaptic stimulation induce depolarization and electrochemical signaling to rapidly alter transcription in the nucleus (5). A slower, more persistent mechanism of signaling to the nucleus involves the transport of soluble molecules from stimulated synapses to the nucleus (6, 7). Recent studies have indicated that this type of transport may involve the active nuclear import pathway (8-10).In the classical nuclear import pathway, proteins bearing nuclear localization signals (NLSs) bind an adaptor protein of the importin ␣ family, which in turn binds the importin ␤1 nuclear transporter. Importin ␤1 mediates facilitated translocation of this heterotrimeric complex across the nuclear pore. In neurons, importins may also function to carry signals from distal neuronal processes to the soma and into the nucleus (8-11). This finding raises a critical question: what are the synaptically localized cargoes of importins that translocate to the nucleus to alter transcription during synaptic plasticity?One attractive class of potential importin...

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“…Clearly, the localization of ERK and pERK1/2 differs significantly from that of proteins containing a nuclear localization signal (NLS) such as nuclear factor B or NFAT. Active transport of such proteins causes them to localize virtually exclusively to the nucleus (42,43).…”

Section: Phosphorylation and Nuclear Translocation Of Endogenousmentioning

confidence: 99%

Diffusion and Not Active Transport Underlies and Limits ERK1/2 Synapse-to-Nucleus Signaling in Hippocampal Neurons

Wiegert

Bengtson

Bading

2007

Journal of Biological Chemistry

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The propagation of signals from synapses and dendrites to the nucleus is crucial for long lasting adaptive changes in the nervous system. The ERK-MAPK pathway can link neuronal activity and cell surface receptor activation to the regulation of gene transcription, and it is often considered the principal mediator of synapse-to-nucleus communication in late-phase plasticity and learning. However, the mechanisms underlying ERK1/2 trafficking in dendrites and nuclear translocation in neurons remain to be determined leaving it unclear whether ERK1/2 activated at the synapse can contribute to nuclear signaling and transcriptional regulation. Using the photobleachable and photoactivable fluorescent tag Dronpa on ERK1 and ERK2, we show here that ERK1/2 translocation to the nucleus of hippocampal neurons is induced by the stimulation of N-methyl-D-aspartate receptors or TrkB stimulation and is apparently mediated by facilitated diffusion. In contrast, ERK1/2 trafficking within dendrites is not signal-regulated and is mediated by passive diffusion. Within dendrites, the reach of a locally activated pool of ERK1/2 is very limited and follows an exponential decay with distance. These results indicate that successful signal propagation to the nucleus by the ERK-MAPK pathway depends on the distance of the nucleus from the site of ERK1/2 activation. ERK1/2 activated within or near the soma may rapidly reach the nucleus to induce gene expression, whereas ERK1/2 activated at distal synapses may only contribute to local signaling.The extracellular signal-regulated kinase/mitogen-activated protein (ERK-MAP) 2 kinase cascade is a multifunctional signaling module that plays an important role in the development, differentiation, and proliferation of many cell types. In the nervous system, ERK1 and ERK2 are activated by trophic factors, such as BDNF (1) and electrical activity causing calcium influx into neurons through NMDA receptors or voltage-gated calcium channels (2, 3). A large body of literature has implicated the ERK-MAP kinase pathway in numerous activity-driven neuronal processes, including neuronal survival, synaptic plasticity and learning (4, 5), circadian rhythms (6), pain (7), and addiction (8). ERK1/2 can act locally near the site of activation by cell surface receptors or ion channels to control, for example, the trafficking of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (9). Another putative role of ERK1/2 in the nervous system is to propagate signals generated at the synapse along the dendrites toward and into the cell nucleus, where it leads to induction of gene transcription. ERK1/2 can phosphorylate several transcription factors, including the ternary complex factors Elk-1 (10, 11) and SAP-1/2 (12), as well as c-Jun (13) and c-Fos (14). The cAMP-response element-binding protein (CREB) is also a target of the ERK-MAP kinase pathway, although CREB phosphorylation on its activator site serine 133 is catalyzed not by ERK1/2 but by the ERK1/2-regulated kinases ribosomal protein S6 kinase 2 and mitog...

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Retrograde Transport of Transcription Factor NF-κB in Living Neurons

Abstract: The mechanism by which signals such as those produced by glutamate are transferred to the nucleus may involve direct transport of an activated transcription factor to trigger long-term transcriptional changes.

Cited by 105 publications

References 54 publications

Regulation of Nuclear Factor κB in the Hippocampus by Group I Metabotropic Glutamate Receptors

Regulation of Nuclear Factor κB in the Hippocampus by Group I Metabotropic Glutamate Receptors

Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons

Diffusion and Not Active Transport Underlies and Limits ERK1/2 Synapse-to-Nucleus Signaling in Hippocampal Neurons

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