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  • Review Article
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Regulation of transcription factors by neuronal activity

Key Points

  • Synaptic activity regulates the expression of neuronal gene products that are important for neuronal survival and differentiation, synaptogenesis and complex behaviour. Diverse mechanisms modulate the activity of positive and negative transcriptional regulators.

  • Members of the cyclic-AMP-response-element-binding protein (CREB) family of transcription factors are among the most widely studied activity-dependent transcription factors in the brain. It is unclear how synaptic activity in dendrites activates CREB in the nucleus. Protein complexes associated with plasma-membrane calcium channels seem to be crucial for transducing calcium influx into changes in gene transcription. The selective association of signalling molecules with distinct calcium channels might explain how the route of calcium entry can influence the ability of calcium to activate gene transcription.

  • CREB is activated by activity-dependent phosphorylation at Ser133, which works, at least in part, through the inducible recruitment of the transcriptional coactivator CREB-binding protein (CBP). Neuronal stimuli that cause the influx of calcium lead to the phosphorylation of CREB at additional residues, including Ser142 and Ser143, which block the binding of the KIX domain of CBP to CREB Ser133. So, CREB might also mediate transcription through alternative mechanisms, independently of CBP recruitment.

  • Stimuli induce diverse biological responses, in part by initiating distinct programmes of gene expression. In neurons, many stimuli induce the expression of c-Fos, but only stimuli that lead to the elevation of intracellular calcium induce Bdnf expression. Transcription of Bdnf is cooperatively regulated by a number of factors, including the transcription factor CaRF (calcium-response factor). CaRF is activated in a calcium- and neuron-selective manner, and might confer stimulus and cell-type selectivity on the induction of its target genes.

  • Calcium can also directly regulate transcription factors. Calcium binding to the transcriptional repressor DREAM (downstream-response-element-antagonist modulator) inhibits the ability of DREAM to bind DNA, relieving the repression of target genes such as prodynorphin. Dream-knockout mice show altered pain perception and enhanced expression of dynorphin, indicating that DREAM is a crucial transcriptional regulator of prodynorphin in vivo.

  • Neuronal activity also activates transcription by relocalizing latent transcription factors from the cytoplasm to the nucleus. NFAT (nuclear factor of activated T cells) and NF-κB (nuclear factor-κB) are expressed in the nervous system and relocate to the nucleus in response to neuronal stimuli. Although the role of these factors in neural function is unclear, their distribution outside the nucleus, where they can respond to local stimuli, indicates a potential involvement in processes such as axon guidance and synaptic modulation.

  • Neuronal stimuli modulate the chromatin architecture of target promoters, thereby regulating transcriptional initiation. Chromatin structure can be altered by post-translational modifications that are mediated by inducibly recruited coactivator or corepressor molecules. Among the best-characterized chromatin modifications is the reversible acetylation of histone proteins. This modification is controlled by the opposing actions of cellular histone acetyl-transferases (HATs) and histone deacetylases (HDACs). The activity of both HATs and HDACs is regulated by calcium signalling, and further work will be required to determine the physiological role of these transcriptional regulators in neuronal function.

  • Future advances in our understanding of how signal-specific transcriptional programmes are generated and maintained in the developing and mature nervous system should benefit from the increased use of new approaches, such as bioinformatics, chromatin immunoprecipitation and gene-expression profiling. The development and use of new imaging techniques, together with improved targeted animal models, should expand our understanding of the physiological roles of activity-dependent transcription in brain development and function.

Abstract

Synaptic activity regulates the expression of a set of neuronal gene products that are important for neuronal survival and differentiation, synaptogenesis and, ultimately, complex behaviour. Activity-dependent signalling pathways induce neuronal gene transcription by modulating the function of both transcriptional activators and repressors, and recent studies have revealed significant diversity in the mechanisms that control the activity of these transcriptional regulators. Investigators have begun to elucidate the distinct functions of individual activity-regulated transcription factors, and to explore how these factors cooperate to provide stimulus specificity in the initiation of neuronal transcriptional programmes.

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Figure 1: Activation of CREB-dependent gene transcription.
Figure 2: Model of the local activation of signalling pathways by plasma-membrane calcium channels.
Figure 3: Model of the formation of signal-specific transcriptional complexes.
Figure 4: Mechanisms of NFAT and NF-κB regulation.
Figure 5: Calcium regulation of HDAC complexes.

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Acknowledgements

M.E.G. acknowledges the generous support of the F. M. Kirby Foundation to the Division of Neuroscience. This work was supported by a Mental Retardation Research Center grant and a National Institutes of Health grant to M.E.G., an American Cancer Society postdoctoral fellowship to A.E.W., and a Helen Hay Whitney postdoctoral fellowship to E.C.G. We thank P. Greer, A. Brunet, C. Cowan and J. Kornhauser for critical reading of the manuscript. We apologize to our colleagues whose original research could not be cited owing to space limitations.

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Correspondence to Michael E. Greenberg.

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DATABASES

LocusLink

14-3-3

AMPARs

β-amyloid

ATF1

BDNF

Cabin1

calcineurin

calmodulin

CaMKI

CaMKII

CaMKIV

CaRF

casein kinase 1

CBP

c-Fos

CREB

c-Rel

CREM

DREAM

EphB

FosB

GATA

GSK3

HDAC1

HDAC2

HDAC4

HDAC5

HDAC7

HDAC9

IκBs

IKK

IP3R1

MAPK

MEF2

MEK

nAChRs

NFATc2

NFATc4

NF-κB1

NF-κB2

NGF

nNOS

NR1

NR2A

NR2B

κ-opioid receptors

p300

Pdyn

Per

PKA

PP1

PP2A

presenilin

Ras

RelA

RelB

Rsk

RyR

Sin3

Src

SRF

TNF-α

TNFR

VGCCs

OMIM

Alzheimer's disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

chromatin remodelling and histone modification in transcription regulation

protein phosphorylation and long-term synaptic plasticity

protein synthesis and long-term synaptic plasticity

transcriptional gene regulation in eukaryotes

Michael Greenberg's lab

Glossary

CIRCADIAN RHYTHMS

Biological rhythms of physiology and behaviour that have a periodicity of 24 hours and are controlled by a clock mechanism in the suprachiasmatic nucleus of the brain.

IMMEDIATE–EARLY GENES

Genes that are induced rapidly and transiently in the absence of de novo protein synthesis. Many immediate–early genes, such as c-Fos, control the transcription of other genes, and thereby provide the early stages in the control of the production of specific proteins.

NEUROTROPHINS

A family of secreted molecules (BDNF, NGF, NT3 and NT4/5) that promote neuronal survival.

DOMINANT NEGATIVE

Describes a mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

APOPTOSIS

A process of cell death that is characterized by the activation of a genetically encoded cell-suicide programme.

LONG-TERM POTENTIATION

(LTP). An enduring increase in postsynaptic responsiveness as a result of high-frequency (tetanic) stimulation of presynaptic neurons. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of postsynaptic-cell population spike. LTP is most often studied in the hippocampus and is often considered to be the cellular basis of learning and memory.

LONG-TERM DEPRESSION

(LTD). An enduring weakening of synaptic strength that is thought to interact with long-term potentiation (LTP) in the cellular mechanisms of learning and memory in structures such as the hippocampus and cerebellum. Unlike LTP, which is produced by brief high-frequency stimulation, LTD can be produced by long-term, low-frequency stimulation.

IQ DOMAIN

A small structural domain that mediates interactions with calmodulin. The motif only loosely defines the amino-acid sequence at 5 of 11 possible residues. Different IQ domains bind calmodulin at varying intracellular Ca2+ concentrations or independently of Ca2+.

TRANSCRIPTIONAL COACTIVATOR

A protein that assists in the recruitment of RNA polymerase II to promoters by associating with transcription factors that are bound to sequence-specific DNA elements.

KID AND KIX DOMAINS

The protein interaction domains of CREB and CBP. The kinase-inducible domain (KID) of CREB contains Ser133, which is phosphorylated in response to many extracellular stimuli. Phosphorylation at Ser133 recruits CBP through binding of its KIX domain.

CYTOKINES

In general terms, cytokines are proteins made by cells that affect the behaviour of other cells. They are produced mainly by the immune system.

PC12 CELLS

Neuron-like cells that are derived from a malignant neural crest tumour (a phaeochromocytoma).

EF HAND

A Ca2+-binding domain that was originally identified in parvalbumin. Also known as the helix–loop–helix domain. The loop can accommodate Ca2+ by coordination through several amino acids in a pentagonal pyramid.

PRODYNORPHIN

The preprocessed form of the peptide dynorphin, which mediates pain sensation by binding to the κ-opioid receptor.

REPORTER GENE

A gene that encodes an easily assayed product. It is coupled to the upstream sequence of another gene, and can then be transfected into cells to identify factors that activate response elements in the upstream region of the gene of interest.

STERIC HINDRANCE

The prevention of a reaction between different molecules as a result of their sizes or spatial disposition.

MHC CLASS I GENES

Major histocompatibility complex (MHC) class I genes are required for the presentation of antigen to T cells in the immune system; their function in the immunologically privileged CNS is largely unknown.

CHROMATIN

A complex of DNA, histones and non-histone proteins that is found in the nucleus of the eukaryotic cell.

MASS SPECTROMETRY

A technique in which a compound is bombarded with an electron beam of sufficient energy to fragment the molecule. The cations that are produced are accelerated in a vacuum through a magnetic field, and sorted on the basis of mass-to-charge ratio. The ratio is roughly equivalent to the molecular weight of the fragment.

CHROMATIN IMMUNOPRECIPITATION

A technique that is used to identify transcription factors bound to chromatin.

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West, A., Griffith, E. & Greenberg, M. Regulation of transcription factors by neuronal activity. Nat Rev Neurosci 3, 921–931 (2002). https://doi.org/10.1038/nrn987

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