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West, Anne Elizabeth

Overview:

The long term goal of our laboratory is to understand at a cellular/molecular level how neuronal activity regulates the formation and maturation of synapses during brain development, and ultimately to use genetic model systems to understand how defects in this developmental process lead to cognitive dysfunction.

Positions:

Associate Professor of Neurobiology

Neurobiology
School of Medicine

Faculty Network Member of the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.A. 1989

B.A. — Cornell University

M.D. 1998

M.D. — Harvard University

Ph.D. 1998

Ph.D. — Harvard University

News:

Grants:

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1997
End Date
June 30, 2022

Chromatin Mechanisms of Neuronal Maturation

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2017
End Date
April 30, 2022

Basic predoctoral training in neuroscience

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Training Faculty
Start Date
July 01, 1992
End Date
June 30, 2018

Regulation of Cocaine Reward and Reinforcement by MeCP2

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2013
End Date
December 31, 2017

Genome-Wide Mapping of Enhancer Elements for Neuronal Differentiation Genes

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2013
End Date
June 30, 2016

Training in Fundamental &Translational Neuroscience

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Training Faculty
Start Date
July 01, 2005
End Date
February 29, 2016

Amphetamine-Induced Transcriptional Plasticity in Striatal GABAergic Interneurons

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2012
End Date
January 31, 2015

Regulation of response to chronic antidepressant treatment by MeCP2

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 22, 2012
End Date
August 31, 2014

Development of a Platform for Imaging Activity-Dependent Transcription in Neurons

Administered By
Neurobiology
AwardedBy
National Science Foundation
Role
Co Investigator
Start Date
August 01, 2011
End Date
July 31, 2013

Behavioral and Synaptic Consequences of MeCP2 Phosphorylation

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 01, 2010
End Date
December 31, 2011

Epigenetic regulation of transcriptional repression by drugs of abuse

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 29, 2006
End Date
June 30, 2011

A role for the epigenetic factor MeCP2 in neural response to psychostimulants

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2008
End Date
August 31, 2010
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Publications:

BayFish: Bayesian inference of transcription dynamics from population snapshots of single-molecule RNA FISH in single cells.

Single-molecule RNA fluorescence in situ hybridization (smFISH) provides unparalleled resolution in the measurement of the abundance and localization of nascent and mature RNA transcripts in fixed, single cells. We developed a computational pipeline (BayFish) to infer the kinetic parameters of gene expression from smFISH data at multiple time points after gene induction. Given an underlying model of gene expression, BayFish uses a Monte Carlo method to estimate the Bayesian posterior probability of the model parameters and quantify the parameter uncertainty given the observed smFISH data. We tested BayFish on synthetic data and smFISH measurements of the neuronal activity-inducible gene Npas4 in primary neurons.

Authors
Gómez-Schiavon, M; Chen, L-F; West, AE; Buchler, NE
MLA Citation
Gómez-Schiavon, M, Chen, L-F, West, AE, and Buchler, NE. "BayFish: Bayesian inference of transcription dynamics from population snapshots of single-molecule RNA FISH in single cells." Genome biology 18.1 (September 4, 2017): 164-.
PMID
28870226
Source
epmc
Published In
Genome Biology: biology for the post-genomic era
Volume
18
Issue
1
Publish Date
2017
Start Page
164
DOI
10.1186/s13059-017-1297-9

Transcribing the connectome: roles for transcription factors and chromatin regulators in activity-dependent synapse development.

The wiring of synaptic connections in the developing mammalian brain is shaped by both intrinsic and extrinsic signals. One point where these regulatory pathways converge is via the sensory experience-dependent regulation of new gene transcription. Recent studies have elucidated a number of molecular mechanisms that allow nuclear transcription factors and chromatin regulatory proteins to encode aspects of specificity in experience-dependent synapse development. Here we review the evidence for the transcriptional mechanisms that sculpt activity-dependent aspects of synaptic connectivity during postnatal development and discuss how disruption of these processes is associated with aberrant brain development in autism and intellectual disability.

Authors
Chen, L-F; Zhou, AS; West, AE
MLA Citation
Chen, L-F, Zhou, AS, and West, AE. "Transcribing the connectome: roles for transcription factors and chromatin regulators in activity-dependent synapse development." Journal of neurophysiology 118.2 (August 2017): 755-770. (Review)
PMID
28490640
Source
epmc
Published In
Journal of neurophysiology
Volume
118
Issue
2
Publish Date
2017
Start Page
755
End Page
770
DOI
10.1152/jn.00067.2017

Regulation and function of MeCP2 Ser421 phosphorylation in U50488-induced conditioned place aversion in mice.

Phosphorylation of the methyl DNA-binding protein MeCP2 at Ser421 (pMeCP2-S421) is induced in corticolimbic brain regions during exposure to drugs of abuse and modulates reward-driven behaviors. However, whether pMeCP2-S421 is also involved in behavioral adaptations to aversive drugs is unknown.Our goal was to establish the role and regulation of pMeCP2-S421 in corticolimbic brain regions of mice upon acute treatment with the kappa opioid receptor agonist U50488 and during the expression of U50488-induced conditioned place aversion (CPA).pMeCP2-S421 levels were measured in the nucleus accumbens (NAc), prelimbic cortex, infralimbic cortex (ILC), and basolateral amygdala (BLA) of male mice after intraperitoneal administration of U50488 and upon the expression of U50488-induced CPA. Fos was measured as marker of neural activity in the same brain regions. U50488-induced CPA and Fos levels were compared between knockin (KI) mice that lack pMeCP2-S421 and their wild-type (WT) littermates.U50488 administration acutely induced pMeCP2-S421 and Fos selectively in the NAc but did not alter MeCP2 levels in any brain region. U50488-induced CPA was associated with decreased pMeCP2-S421 in the ILC and BLA and induced Fos in the BLA. MeCP2 KI mice showed CPA indistinguishable from their WT littermates, but they also showed less BLA Fos induction upon CPA.These data are the first to show that pMeCP2-S421 is induced in the brain acutely after U50488 administration but not upon U50488-induced CPA. Although pMeCP2-S421 is not required for U50488-induced CPA, this phosphorylation event may contribute to molecular plasticities in brain regions that govern aversive behaviors.

Authors
Zannas, AS; Kim, JH; West, AE
MLA Citation
Zannas, AS, Kim, JH, and West, AE. "Regulation and function of MeCP2 Ser421 phosphorylation in U50488-induced conditioned place aversion in mice." Psychopharmacology 234.6 (March 2017): 913-923.
PMID
28116477
Source
epmc
Published In
Psychopharmacology
Volume
234
Issue
6
Publish Date
2017
Start Page
913
End Page
923
DOI
10.1007/s00213-017-4527-7

Editing the Neuronal Genome: a CRISPR View of Chromatin Regulation in Neuronal Development, Function, and Plasticity.

The dynamic orchestration of gene expression is crucial for the proper differentiation, function, and adaptation of cells. In the brain, transcriptional regulation underlies the incredible diversity of neuronal cell types and contributes to the ability of neurons to adapt their function to the environment. Recently, novel methods for genome and epigenome editing have begun to revolutionize our understanding of gene regulatory mechanisms. In particular, the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has proven to be a particularly accessible and adaptable technique for genome engineering. Here, we review the use of CRISPR/Cas9 in neurobiology and discuss how these studies have advanced understanding of nervous system development and plasticity. We cover four especially salient applications of CRISPR/Cas9: testing the consequences of enhancer mutations, tagging genes and gene products for visualization in live cells, directly activating or repressing enhancers in vivo, and manipulating the epigenome. In each case, we summarize findings from recent studies and discuss evolving adaptations of the method.

Authors
Yang, MG; West, AE
MLA Citation
Yang, MG, and West, AE. "Editing the Neuronal Genome: a CRISPR View of Chromatin Regulation in Neuronal Development, Function, and Plasticity." The Yale journal of biology and medicine 89.4 (December 23, 2016): 457-470. (Review)
Website
http://hdl.handle.net/10161/13332
PMID
28018138
Source
epmc
Published In
The Yale journal of biology and medicine
Volume
89
Issue
4
Publish Date
2016
Start Page
457
End Page
470

The transcription factor calcium-response factor limits NMDA receptor-dependent transcription in the developing brain.

Neuronal activity sculpts brain development by inducing the transcription of genes such as brain-derived neurotrophic factor (Bdnf) that modulate the function of synapses. Sensory experience is transduced into changes in gene transcription via the activation of calcium signaling pathways downstream of both L-type voltage-gated calcium channels (L-VGCCs) and NMDA-type glutamate receptors (NMDARs). These signaling pathways converge on the regulation of transcription factors including calcium-response factor (CaRF). Although CaRF is dispensable for the transcriptional induction of Bdnf following the activation of L-VGCCs, here we show that the loss of CaRF leads to enhanced NMDAR-dependent transcription of Bdnf as well as Arc. We identify the NMDAR subunit-encoding gene Grin3a as a regulatory target of CaRF, and we show that expression of both Carf and Grin3a is depressed by the elevation of intracellular calcium, linking the function of this transcriptional regulatory pathway to neuronal activity. We find that light-dependent activation of Bdnf and Arc transcription is enhanced in the visual cortex of young CaRF knockout mice, suggesting a role for CaRF-dependent dampening of NMDAR-dependent transcription in the developing brain. Finally, we demonstrate that enhanced Bdnf expression in CaRF-lacking neurons increases inhibitory synapse formation. Taken together, these data reveal a novel role for CaRF as an upstream regulator of NMDAR-dependent gene transcription and synapse formation in the developing brain. NMDARs promote brain development by inducing the transcription of genes, including brain-derived neurotrophic factor (BDNF). We show that the transcription factor calcium-response factor (CaRF) limits NMDAR-dependent BDNF induction by regulating expression of the NMDAR subunit GluN3A. Loss of CaRF leads to enhanced BDNF-dependent GABAergic synapse formation indicating the importance of this process for brain development. Our observation that both CaRF and GluN3A are down-regulated by intracellular calcium suggests that this may be a mechanism for experience-dependent modulation of synapse formation.

Authors
Lyons, MR; Chen, L-F; Deng, JV; Finn, C; Pfenning, AR; Sabhlok, A; Wilson, KM; West, AE
MLA Citation
Lyons, MR, Chen, L-F, Deng, JV, Finn, C, Pfenning, AR, Sabhlok, A, Wilson, KM, and West, AE. "The transcription factor calcium-response factor limits NMDA receptor-dependent transcription in the developing brain." Journal of neurochemistry 137.2 (April 2016): 164-176.
PMID
26826701
Source
epmc
Published In
Journal of Neurochemistry
Volume
137
Issue
2
Publish Date
2016
Start Page
164
End Page
176
DOI
10.1111/jnc.13556

Genomic Views of Transcriptional Enhancers: Essential Determinants of Cellular Identity and Activity-Dependent Responses in the CNS.

Sprinkled throughout the genome are a million regulatory sequences called transcriptional enhancers that activate gene promoters in the right cells, at the right time. Enhancers endow the brain with its incredible diversity of cell types and also translate neural activity into gene induction. Thanks to rapid advances in genomic technologies, it is now possible to identify thousands of enhancers rapidly, test their transcriptional function en masse, and address their neurobiological functions via genome editing. Enhancers also promise to be a great technological opportunity for neuroscience, offering the potential for cell-type-specific genetic labeling and manipulation without the need for transgenesis. The objective of this review and the accompanying 2015 SfN mini-symposium is to highlight the use of new and emerging genomic technologies to probe enhancer function in the nervous system.Transcriptional enhancers turn on genes in the right cells, at the right time. Enhancers are also the genomic sequences that encode the incredible diversity of cell types in the brain and enable the brain to turn genes on in response to new experiences. New technology enables enhancers to be found and manipulated. The study of enhancers promises to inform our understanding of brain development and function. The application of enhancer technology holds promise in accelerating basic neuroscience research and enabling gene therapies to be targeted to specific cell types in the brain.

Authors
Gray, JM; Kim, T-K; West, AE; Nord, AS; Markenscoff-Papadimitriou, E; Lomvardas, S
MLA Citation
Gray, JM, Kim, T-K, West, AE, Nord, AS, Markenscoff-Papadimitriou, E, and Lomvardas, S. "Genomic Views of Transcriptional Enhancers: Essential Determinants of Cellular Identity and Activity-Dependent Responses in the CNS." The Journal of neuroscience : the official journal of the Society for Neuroscience 35.41 (October 2015): 13819-13826. (Review)
PMID
26468181
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
35
Issue
41
Publish Date
2015
Start Page
13819
End Page
13826
DOI
10.1523/jneurosci.2622-15.2015

Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum.

To identify chromatin mechanisms of neuronal differentiation, we characterized chromatin accessibility and gene expression in cerebellar granule neurons (CGNs) of the developing mouse. We used DNase-seq to map accessibility of cis-regulatory elements and RNA-seq to profile transcript abundance across postnatal stages of neuronal differentiation in vivo and in culture. We observed thousands of chromatin accessibility changes as CGNs differentiated, and verified, using H3K27ac ChIP-seq, reporter gene assays and CRISPR-mediated activation, that many of these regions function as neuronal enhancers. Motif discovery in differentially accessible chromatin regions suggested a previously unknown role for the Zic family of transcription factors in CGN maturation. We confirmed the association of Zic with these elements by ChIP-seq and found, using knockdown, that Zic1 and Zic2 are required for coordinating mature neuronal gene expression patterns. Together, our data reveal chromatin dynamics at thousands of gene regulatory elements that facilitate the gene expression patterns necessary for neuronal differentiation and function.

Authors
Frank, CL; Liu, F; Wijayatunge, R; Song, L; Biegler, MT; Yang, MG; Vockley, CM; Safi, A; Gersbach, CA; Crawford, GE; West, AE
MLA Citation
Frank, CL, Liu, F, Wijayatunge, R, Song, L, Biegler, MT, Yang, MG, Vockley, CM, Safi, A, Gersbach, CA, Crawford, GE, and West, AE. "Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum." Nature neuroscience 18.5 (May 2015): 647-656.
PMID
25849986
Source
epmc
Published In
Nature Neuroscience
Volume
18
Issue
5
Publish Date
2015
Start Page
647
End Page
656
DOI
10.1038/nn.3995

Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling.

Mutations in PARKIN (PARK2), an ubiquitin ligase, cause early onset Parkinson disease. Parkin was shown to bind, ubiquitinate, and target depolarized mitochondria for destruction by autophagy. This process, mitophagy, is considered crucial for maintaining mitochondrial integrity and suppressing Parkinsonism. Here, we report that under moderate mitochondrial stress, parkin does not translocate to mitochondria to induce mitophagy; rather, it stimulates mitochondrial connectivity. Mitochondrial stress-induced fusion requires PINK1 (PARK6), mitofusins, and parkin ubiquitin ligase activity. Upon exposure to mitochondrial toxins, parkin binds α-synuclein (PARK1), and in conjunction with the ubiquitin-conjugating enzyme Ubc13, stimulates K63-linked ubiquitination. Importantly, α-synuclein inactivation phenocopies parkin overexpression and suppresses stress-induced mitochondria fission, whereas Ubc13 inactivation abrogates parkin-dependent mitochondrial fusion. The convergence of parkin, PINK1, and α-synuclein on mitochondrial dynamics uncovers a common function of these PARK genes in the mitochondrial stress response and provides a potential physiological basis for the prevalence of α-synuclein pathology in Parkinson disease.

Authors
Norris, KL; Hao, R; Chen, L-F; Lai, C-H; Kapur, M; Shaughnessy, PJ; Chou, D; Yan, J; Taylor, JP; Engelender, S; West, AE; Lim, K-L; Yao, T-P
MLA Citation
Norris, KL, Hao, R, Chen, L-F, Lai, C-H, Kapur, M, Shaughnessy, PJ, Chou, D, Yan, J, Taylor, JP, Engelender, S, West, AE, Lim, K-L, and Yao, T-P. "Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling." The Journal of biological chemistry 290.22 (May 2015): 13862-13874.
PMID
25861987
Source
epmc
Published In
The Journal of biological chemistry
Volume
290
Issue
22
Publish Date
2015
Start Page
13862
End Page
13874
DOI
10.1074/jbc.m114.634063

Cocaine shapes chromatin landscapes via Tet1.

Authors
West, AE
MLA Citation
West, AE. "Cocaine shapes chromatin landscapes via Tet1." Nature neuroscience 18.4 (April 2015): 478-480.
PMID
25811475
Source
epmc
Published In
Nature Neuroscience
Volume
18
Issue
4
Publish Date
2015
Start Page
478
End Page
480
DOI
10.1038/nn.3985

Core and region-enriched networks of behaviorally regulated genes and the singing genome.

Songbirds represent an important model organism for elucidating molecular mechanisms that link genes with complex behaviors, in part because they have discrete vocal learning circuits that have parallels with those that mediate human speech. We found that ~10% of the genes in the avian genome were regulated by singing, and we found a striking regional diversity of both basal and singing-induced programs in the four key song nuclei of the zebra finch, a vocal learning songbird. The region-enriched patterns were a result of distinct combinations of region-enriched transcription factors (TFs), their binding motifs, and presinging acetylation of histone 3 at lysine 27 (H3K27ac) enhancer activity in the regulatory regions of the associated genes. RNA interference manipulations validated the role of the calcium-response transcription factor (CaRF) in regulating genes preferentially expressed in specific song nuclei in response to singing. Thus, differential combinatorial binding of a small group of activity-regulated TFs and predefined epigenetic enhancer activity influences the anatomical diversity of behaviorally regulated gene networks.

Authors
Whitney, O; Pfenning, AR; Howard, JT; Blatti, CA; Liu, F; Ward, JM; Wang, R; Audet, J-N; Kellis, M; Mukherjee, S; Sinha, S; Hartemink, AJ; West, AE; Jarvis, ED
MLA Citation
Whitney, O, Pfenning, AR, Howard, JT, Blatti, CA, Liu, F, Ward, JM, Wang, R, Audet, J-N, Kellis, M, Mukherjee, S, Sinha, S, Hartemink, AJ, West, AE, and Jarvis, ED. "Core and region-enriched networks of behaviorally regulated genes and the singing genome." Science (New York, N.Y.) 346.6215 (December 2014): 1256780-.
Website
http://hdl.handle.net/10161/11150
PMID
25504732
Source
epmc
Published In
Science
Volume
346
Issue
6215
Publish Date
2014
Start Page
1256780
DOI
10.1126/science.1256780

The histone lysine demethylase Kdm6b is required for activity-dependent preconditioning of hippocampal neuronal survival.

Enzymes that regulate histone lysine methylation play important roles in neuronal differentiation, but little is known about their contributions to activity-regulated gene transcription in differentiated neurons. We characterized activity-regulated expression of lysine demethylases and lysine methyltransferases in the hippocampus of adult male mice following pilocarpine-induced seizure. Pilocarpine drove a 20-fold increase in mRNA encoding the histone H3 lysine 27-specific demethylase Kdm6b selectively in granule neurons of the dentate gyrus, and this induction was recapitulated in cultured hippocampal neurons by bicuculline and 4-aminopyridine (Bic + 4AP) stimulation of synaptic activity. Because activity-regulated gene expression is highly correlated with neuronal survival, we tested the requirement for Kdm6b expression in Bic + 4AP induced preconditioning of neuronal survival. Prior exposure to Bic + 4AP promoted neuronal survival in control neurons upon growth factor withdrawal; however, this effect was ablated when we knocked down Kdm6b expression. Loss of Kdm6b did not disrupt activity-induced expression of most genes, including that of a gene set previously established to promote neuronal survival in this assay. However, using bioinformatic analysis of RNA sequencing data, we discovered that Kdm6b knockdown neurons showed impaired inducibility of a discrete set of genes annotated for their function in inflammation. These data reveal a novel function for Kdm6b in activity-regulated neuronal survival, and they suggest that activity- and Kdm6b-dependent regulation of inflammatory gene pathways may serve as an adaptive pro-survival response to increased neuronal activity.

Authors
Wijayatunge, R; Chen, L-F; Cha, YM; Zannas, AS; Frank, CL; West, AE
MLA Citation
Wijayatunge, R, Chen, L-F, Cha, YM, Zannas, AS, Frank, CL, and West, AE. "The histone lysine demethylase Kdm6b is required for activity-dependent preconditioning of hippocampal neuronal survival." Molecular and cellular neurosciences 61 (July 2014): 187-200.
PMID
24983519
Source
epmc
Published In
Molecular and Cellular Neuroscience
Volume
61
Publish Date
2014
Start Page
187
End Page
200
DOI
10.1016/j.mcn.2014.06.008

Epigenetics in brain function

Authors
West, AE; Orlando, V
MLA Citation
West, AE, and Orlando, V. "Epigenetics in brain function." Neuroscience 264 (April 4, 2014): 1-3.
Source
scopus
Published In
Neuroscience
Volume
264
Publish Date
2014
Start Page
1
End Page
3
DOI
10.1016/j.neuroscience.2014.02.001

Epigenetics and the regulation of stress vulnerability and resilience

The human brain has a remarkable capacity to adapt to and learn from a wide range of variations in the environment. However, environmental challenges can also precipitate psychiatric disorders in susceptible individuals. Why any given experience should induce one brain to adapt while another is edged toward psychopathology remains poorly understood. Like all aspects of psychological function, both nature (genetics) and nurture (life experience) sculpt the brain's response to stressful stimuli. Here we review how these two influences intersect at the epigenetic regulation of neuronal gene transcription, and we discuss how the regulation of genomic DNA methylation near key stress-response genes may influence psychological susceptibility or resilience to environmental stressors. Our goal is to offer a perspective on the epigenetics of stress responses that works to bridge the gap between the study of this molecular process in animal models and its potential usefulness for understanding stress vulnerabilities in humans. © 2013 IBRO.

Authors
Zannas, AS; West, AE
MLA Citation
Zannas, AS, and West, AE. "Epigenetics and the regulation of stress vulnerability and resilience." Neuroscience 264 (April 4, 2014): 157-170. (Review)
Source
scopus
Published In
Neuroscience
Volume
264
Publish Date
2014
Start Page
157
End Page
170
DOI
10.1016/j.neuroscience.2013.12.003

Epigenetics and the regulation of stress vulnerability and resilience.

The human brain has a remarkable capacity to adapt to and learn from a wide range of variations in the environment. However, environmental challenges can also precipitate psychiatric disorders in susceptible individuals. Why any given experience should induce one brain to adapt while another is edged toward psychopathology remains poorly understood. Like all aspects of psychological function, both nature (genetics) and nurture (life experience) sculpt the brain's response to stressful stimuli. Here we review how these two influences intersect at the epigenetic regulation of neuronal gene transcription, and we discuss how the regulation of genomic DNA methylation near key stress-response genes may influence psychological susceptibility or resilience to environmental stressors. Our goal is to offer a perspective on the epigenetics of stress responses that works to bridge the gap between the study of this molecular process in animal models and its potential usefulness for understanding stress vulnerabilities in humans.

Authors
Zannas, AS; West, AE
MLA Citation
Zannas, AS, and West, AE. "Epigenetics and the regulation of stress vulnerability and resilience." Neuroscience 264 (April 2014): 157-170. (Review)
PMID
24333971
Source
epmc
Published In
Neuroscience
Volume
264
Publish Date
2014
Start Page
157
End Page
170
DOI
10.1016/j.neuroscience.2013.12.003

Epigenetics in brain function.

Authors
West, AE; Orlando, V
MLA Citation
West, AE, and Orlando, V. "Epigenetics in brain function." Neuroscience 264 (April 2014): 1-3.
PMID
24525303
Source
epmc
Published In
Neuroscience
Volume
264
Publish Date
2014
Start Page
1
End Page
3
DOI
10.1016/j.neuroscience.2014.02.001

MeCP2 phosphorylation limits psychostimulant-induced behavioral and neuronal plasticity.

The methyl-DNA binding protein MeCP2 is emerging as an important regulator of drug reinforcement processes. Psychostimulants induce phosphorylation of MeCP2 at Ser421; however, the functional significance of this posttranslational modification for addictive-like behaviors was unknown. Here we show that MeCP2 Ser421Ala knock-in mice display both a reduced threshold for the induction of locomotor sensitization by investigator-administered amphetamine and enhanced behavioral sensitivity to the reinforcing properties of self-administered cocaine. These behavioral differences were accompanied in the knock-in mice by changes in medium spiny neuron intrinsic excitability and nucleus accumbens gene expression typically observed in association with repeated exposure to these drugs. These data show that phosphorylation of MeCP2 at Ser421 functions to limit the circuit plasticities in the nucleus accumbens that underlie addictive-like behaviors.

Authors
Deng, JV; Wan, Y; Wang, X; Cohen, S; Wetsel, WC; Greenberg, ME; Kenny, PJ; Calakos, N; West, AE
MLA Citation
Deng, JV, Wan, Y, Wang, X, Cohen, S, Wetsel, WC, Greenberg, ME, Kenny, PJ, Calakos, N, and West, AE. "MeCP2 phosphorylation limits psychostimulant-induced behavioral and neuronal plasticity." The Journal of neuroscience : the official journal of the Society for Neuroscience 34.13 (March 2014): 4519-4527.
PMID
24671997
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
34
Issue
13
Publish Date
2014
Start Page
4519
End Page
4527
DOI
10.1523/jneurosci.2821-13.2014

Rem2 is an activity-dependent negative regulator of dendritic complexity in vivo.

A key feature of the CNS is structural plasticity, the ability of neurons to alter their morphology and connectivity in response to sensory experience and other changes in the environment. How this structural plasticity is achieved at the molecular level is not well understood. We provide evidence that changes in sensory experience simultaneously trigger multiple signaling pathways that either promote or restrict growth of the dendritic arbor; structural plasticity is achieved through a balance of these opposing signals. Specifically, we have uncovered a novel, activity-dependent signaling pathway that restricts dendritic arborization. We demonstrate that the GTPase Rem2 is regulated at the transcriptional level by calcium influx through L-VGCCs and inhibits dendritic arborization in cultured rat cortical neurons and in the Xenopus laevis tadpole visual system. Thus, our results demonstrate that changes in neuronal activity initiate competing signaling pathways that positively and negatively regulate the growth of the dendritic arbor. It is the balance of these opposing signals that leads to proper dendritic morphology.

Authors
Ghiretti, AE; Moore, AR; Brenner, RG; Chen, L-F; West, AE; Lau, NC; Van Hooser, SD; Paradis, S
MLA Citation
Ghiretti, AE, Moore, AR, Brenner, RG, Chen, L-F, West, AE, Lau, NC, Van Hooser, SD, and Paradis, S. "Rem2 is an activity-dependent negative regulator of dendritic complexity in vivo." The Journal of neuroscience : the official journal of the Society for Neuroscience 34.2 (January 2014): 392-407.
PMID
24403140
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
34
Issue
2
Publish Date
2014
Start Page
392
End Page
407
DOI
10.1523/jneurosci.1328-13.2014

BDNF mediates neuroprotection against oxygen-glucose deprivation by the cardiac glycoside oleandrin.

We have previously shown that the botanical drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, provides neuroprotection in both in vitro and in vivo brain slice-based models for focal ischemia (Dunn et al., 2011). Intriguingly, plasma levels of the neurotrophin BDNF were increased in patients treated with PBI-05204 in a phase I clinical trial (Bidyasar et al., 2009). We thus tested the hypothesis that neuroprotection provided by PBI-05204 to rat brain slices damaged by oxygen-glucose deprivation (OGD) is mediated by BDNF. We found, in fact, that exogenous BDNF protein itself is sufficient to protect brain slices against OGD, whereas downstream activation of TrkB receptors for BDNF is necessary for neuroprotection provided by PBI-05204, using three independent methods. Finally, we provide evidence that oleandrin, the principal cardiac glycoside component of PBI-05204, can quantitatively account for regulation of BDNF at both the protein and transcriptional levels. Together, these findings support further investigation of cardiac glycosides in providing neuroprotection in the context of ischemic stroke.

Authors
Van Kanegan, MJ; He, DN; Dunn, DE; Yang, P; Newman, RA; West, AE; Lo, DC
MLA Citation
Van Kanegan, MJ, He, DN, Dunn, DE, Yang, P, Newman, RA, West, AE, and Lo, DC. "BDNF mediates neuroprotection against oxygen-glucose deprivation by the cardiac glycoside oleandrin." The Journal of neuroscience : the official journal of the Society for Neuroscience 34.3 (January 2014): 963-968.
PMID
24431454
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
34
Issue
3
Publish Date
2014
Start Page
963
End Page
968
DOI
10.1523/jneurosci.2700-13.2014

Neurotrophins: transcription and translation.

Neurotrophins are powerful molecules. Small quantities of these secreted proteins exert robust effects on neuronal survival, synapse stabilization, and synaptic function. Key functions of the neurotrophins rely on these proteins being expressed at the right time and in the right place. This is especially true for BDNF, stimulus-inducible expression of which serves as an essential step in the transduction of a broad variety of extracellular stimuli into neuronal plasticity of physiologically relevant brain regions. Here we review the transcriptional and translational mechanisms that control neurotrophin expression with a particular focus on the activity-dependent regulation of BDNF.

Authors
West, AE; Pruunsild, P; Timmusk, T
MLA Citation
West, AE, Pruunsild, P, and Timmusk, T. "Neurotrophins: transcription and translation." Handbook of experimental pharmacology 220 (January 2014): 67-100. (Review)
PMID
24668470
Source
epmc
Published In
Handbook of experimental pharmacology
Volume
220
Publish Date
2014
Start Page
67
End Page
100
DOI
10.1007/978-3-642-45106-5_4

Acquisition of response thresholds for timed performance is regulated by a calcium-responsive transcription factor, CaRF.

Interval timing within the seconds-to-minutes range involves the interaction of the prefrontal cortex and basal ganglia via dopaminergic-glutamatergic pathways. Because the secreted protein brain-derived neurotrophic factor (BDNF) is able to modulate dopamine release as well as glutamatergic activity, we hypothesized that BDNF may be important for these timing mechanisms. Recently, the calcium-responsive transcription factor (CaRF) was identified as an important modulator of BDNF expression in the cerebral cortex. In this study, a strain of Carf knockout mice was evaluated for their ability to acquire the 'Start' and 'Stop' response thresholds under sequential and simultaneous training conditions, using multiple (15-second and 45-second) or single (30-second) target durations in the peak-interval procedure. Both Carf(+/-) and Carf(-/-) mice were impaired in their ability to acquire timed response thresholds relative to Carf(+/+) mice. Additionally, control mice given microinjections of BDNF antisense oligodeoxynucleotide to inhibit protein expression in the prefrontal cortex showed timing impairments during acquisition similar to Carf mice. Together, these results suggest that the inhibitory processes required to update response thresholds and exert temporal control of behavior during acquisition may be dependent on CaRF regulation of genes including Bdnf in cortico-striatal circuits.

Authors
Agostino, PV; Cheng, R-K; Williams, CL; West, AE; Meck, WH
MLA Citation
Agostino, PV, Cheng, R-K, Williams, CL, West, AE, and Meck, WH. "Acquisition of response thresholds for timed performance is regulated by a calcium-responsive transcription factor, CaRF." Genes, brain, and behavior 12.6 (August 2013): 633-644.
PMID
23848551
Source
epmc
Published In
Genes, Brain and Behavior
Volume
12
Issue
6
Publish Date
2013
Start Page
633
End Page
644
DOI
10.1111/gbb.12059

Epigenetics and psychostimulant addiction.

Chronic drug exposure alters gene expression in the brain and produces long-term changes in neural networks that underlie compulsive drug taking and seeking. Exactly how drug-induced changes in synaptic plasticity and subsequent gene expression are translated into persistent neuroadaptations remains unclear. Emerging evidence suggests that complex drug-induced neuroadaptations in the brain are mediated by highly synchronized and dynamic patterns of gene regulation. Recently, it has become clear that epigenetic mechanisms contribute to drug-induced structural, synaptic, and behavioral plasticity by regulating expression of gene networks. Here we review how alterations in histone modifications, DNA methylation, and microRNAs regulate gene expression and contribute to psychostimulant addiction with a focus on the epigenetic mechanisms that regulate brain-derived neurotrophic factor (BDNF) expression following chronic cocaine exposure. Identifying epigenetic signatures that define psychostimulant addiction may lead to novel, efficacious treatments for drug craving and relapse.

Authors
Schmidt, HD; McGinty, JF; West, AE; Sadri-Vakili, G
MLA Citation
Schmidt, HD, McGinty, JF, West, AE, and Sadri-Vakili, G. "Epigenetics and psychostimulant addiction." Cold Spring Harbor perspectives in medicine 3.3 (March 2013): a012047-. (Review)
PMID
23359110
Source
epmc
Published In
Cold Spring Harbor perspectives in medicine
Volume
3
Issue
3
Publish Date
2013
Start Page
a012047
DOI
10.1101/cshperspect.a012047

Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice.

Typical Rett syndrome (RTT) is a pediatric disorder caused by loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. The demonstrated reversibility of RTT-like phenotypes in mice suggests that MECP2 gene replacement is a potential therapeutic option in patients. We report improvements in survival and phenotypic severity in Mecp2-null male mice after neonatal intracranial delivery of a single-stranded (ss) AAV9/chicken β-actin (CBA)-MECP2 vector. Median survival was 16.6 weeks for MECP2-treated versus 9.3 weeks for green fluorescent protein (GFP)-treated mice. ssAAV9/CBA-MECP2-treated mice also showed significant improvement in the phenotype severity score, in locomotor function, and in exploratory activity, as well as a normalization of neuronal nuclear volume in transduced cells. Wild-type (WT) mice receiving neonatal injections of the same ssAAV9/CBA-MECP2 vector did not show any significant deficits, suggesting a tolerance for modest MeCP2 overexpression. To test a MECP2 gene replacement approach in a manner more relevant for human translation, a self-complementary (sc) adeno-associated virus (AAV) vector designed to drive MeCP2 expression from a fragment of the Mecp2 promoter was injected intravenously (IV) into juvenile (4-5 weeks old) Mecp2-null mice. While the brain transduction efficiency in juvenile mice was low (~2-4% of neurons), modest improvements in survival were still observed. These results support the concept of MECP2 gene therapy for RTT.

Authors
Gadalla, KKE; Bailey, MES; Spike, RC; Ross, PD; Woodard, KT; Kalburgi, SN; Bachaboina, L; Deng, JV; West, AE; Samulski, RJ; Gray, SJ; Cobb, SR
MLA Citation
Gadalla, KKE, Bailey, MES, Spike, RC, Ross, PD, Woodard, KT, Kalburgi, SN, Bachaboina, L, Deng, JV, West, AE, Samulski, RJ, Gray, SJ, and Cobb, SR. "Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice." Molecular therapy : the journal of the American Society of Gene Therapy 21.1 (January 2013): 18-30.
PMID
23011033
Source
epmc
Published In
Molecular Therapy
Volume
21
Issue
1
Publish Date
2013
Start Page
18
End Page
30
DOI
10.1038/mt.2012.200

Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice

Typical Rett syndrome (RTT) is a pediatric disorder caused by loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. The demonstrated reversibility of RTT-like phenotypes in mice suggests that MECP2 gene replacement is a potential therapeutic option in patients. We report improvements in survival and phenotypic severity in Mecp2-null male mice after neonatal intracranial delivery of a single-stranded (ss) AAV9/chicken β-actin (CBA)-MECP2 vector. Median survival was 16.6 weeks for MECP2-treated versus 9.3 weeks for green fluorescent protein (GFP)-treated mice. ssAAV9/CBA-MECP2-treated mice also showed significant improvement in the phenotype severity score, in locomotor function, and in exploratory activity, as well as a normalization of neuronal nuclear volume in transduced cells. Wild-type (WT) mice receiving neonatal injections of the same ssAAV9/CBA-MECP2 vector did not show any significant deficits, suggesting a tolerance for modest MeCP2 overexpression. To test a MECP2 gene replacement approach in a manner more relevant for human translation, a self-complementary (sc) adeno-associated virus (AAV) vector designed to drive MeCP2 expression from a fragment of the Mecp2 promoter was injected intravenously (IV) into juvenile (4-5 weeks old) Mecp2-null mice. While the brain transduction efficiency in juvenile mice was low (∼2-4% of neurons), modest improvements in survival were still observed. These results support the concept of MECP2 gene therapy for RTT. © The American Society of Gene & Cell Therapy.

Authors
Gadalla, KK; Bailey, ME; Spike, RC; Ross, PD; Woodard, KT; Kalburgi, SN; Bachaboina, L; Deng, JV; West, AE; Samulski, RJ; Gray, SJ; Cobb, SR
MLA Citation
Gadalla, KK, Bailey, ME, Spike, RC, Ross, PD, Woodard, KT, Kalburgi, SN, Bachaboina, L, Deng, JV, West, AE, Samulski, RJ, Gray, SJ, and Cobb, SR. "Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice." Molecular Therapy 21.1 (2013): 18-30.
Source
scival
Published In
Molecular Therapy
Volume
21
Issue
1
Publish Date
2013
Start Page
18
End Page
30
DOI
10.1038/mt.2012.200

Epigenetics and psychostimulant addiction

Chronic drug exposure alters gene expression in the brain and produces long-term changes in neural networks that underlie compulsive drug taking and seeking. Exactly how druginduced changes in synaptic plasticity and subsequent gene expression are translated into persistent neuroadaptations remains unclear. Emerging evidence suggests that complex drug-induced neuroadaptations in the brain are mediated by highly synchronized and dynamic patterns of gene regulation. Recently, it has become clear that epigenetic mechanisms contribute to drug-induced structural, synaptic, and behavioral plasticity by regulating expression of gene networks. Herewe reviewhowalterations in histone modifications,DNA methylation, and microRNAs regulate gene expression and contribute to psychostimulant addiction with a focus on the epigenetic mechanisms that regulate brain-derived neurotrophic factor (BDNF) expression following chronic cocaine exposure. Identifying epigenetic signatures that define psychostimulant addictionmay lead to novel, efficacious treatments for drug craving and relapse. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

Authors
Schmidt, HD; McGinty, JF; West, AE; Sadri-Vakili, G
MLA Citation
Schmidt, HD, McGinty, JF, West, AE, and Sadri-Vakili, G. "Epigenetics and psychostimulant addiction." Cold Spring Harbor Perspectives in Medicine 3.3 (2013).
Source
scival
Published In
Cold Spring Harbor perspectives in medicine
Volume
3
Issue
3
Publish Date
2013
DOI
10.1101/cshperspect.a012047

Spectral-domain differential interference contrast (SD-DIC) microscopy for measuring live cell dynamics

We present live cell imaging using spectral-domain differential interference contrast microscopy, a novel technique for high-resolution, quantitative measurement of optical pathlength gradients. Imaging and dynamic monitoring of live neurons and cardiomyocytes were demonstrated. © 2012 OSA.

Authors
Zhu, Y; Lyons, MR; West, AE; Satterwhite, LL; Wax, A
MLA Citation
Zhu, Y, Lyons, MR, West, AE, Satterwhite, LL, and Wax, A. "Spectral-domain differential interference contrast (SD-DIC) microscopy for measuring live cell dynamics." Biomedical Optics, BIOMED 2012 (December 1, 2012).
Source
scopus
Published In
Biomedical Optics, BIOMED 2012
Publish Date
2012

Phosphorylation of MeCP2 at Ser421 contributes to chronic antidepressant action.

Although tricyclic antidepressants rapidly activate monoaminergic neurotransmission, these drugs must be administered chronically to alleviate symptoms of depression. This observation suggests that molecular mechanisms downstream of monoamine receptor activation, which include the induction of gene transcription, underlie chronic antidepressant-induced changes in behavior. Here we show that methyl-CpG-binding protein 2 (MeCP2) regulates behavioral responses to chronic antidepressant treatment. Imipramine administration induces phosphorylation of MeCP2 at Ser421 (pMeCP2) selectively in the nucleus accumbens and the lateral habenula, two brain regions important for depressive-like behaviors. To test the role of pMeCP2 in depressive-like behaviors, we used male mice that bear a germ-line mutation knocked into the X-linked Mecp2 locus that changes Ser421 to a nonphosphorylatable Ala residue (S421A). MeCP2 S421A knock-in (KI) mice showed increased immobility in forced-swim and tail-suspension tests compared with their wild-type (WT) littermates. However, immobility of both MeCP2 WT and KI mice in forced swim was reduced by acute administration of imipramine, demonstrating that loss of pMeCP2 does not impair acute pharmacological sensitivity to this drug. After chronic social defeat stress, chronic administration of imipramine significantly improved social interaction in the MeCP2 WT mice. In contrast, the MeCP2 KI mice did not respond to chronic imipramine administration. These data suggest novel roles for pMeCP2 in the sensitivity to stressful stimuli and demonstrate that pMeCP2 is required for the effects of chronic imipramine on depressive-like behaviors induced by chronic social defeat stress.

Authors
Hutchinson, AN; Deng, JV; Cohen, S; West, AE
MLA Citation
Hutchinson, AN, Deng, JV, Cohen, S, and West, AE. "Phosphorylation of MeCP2 at Ser421 contributes to chronic antidepressant action." The Journal of neuroscience : the official journal of the Society for Neuroscience 32.41 (October 2012): 14355-14363.
PMID
23055506
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
32
Issue
41
Publish Date
2012
Start Page
14355
End Page
14363
DOI
10.1523/jneurosci.2156-12.2012

Members of the myocyte enhancer factor 2 transcription factor family differentially regulate Bdnf transcription in response to neuronal depolarization.

Transcription of the gene encoding brain-derived neurotropic factor (BDNF) is induced in response to a wide variety of extracellular stimuli via the activation of a complex array of transcription factors. However, to what degree individual transcription factors confer specificity upon the regulation of Bdnf is poorly understood. Previous studies have shown that members of the myocyte enhancer factor 2 (MEF2) transcription factor family bind a regulatory element upstream of Bdnf promoter I and associate with an unknown binding site in Bdnf promoter IV. Here we identify calcium-response element 1 as the MEF2 binding site in promoter IV of the Bdnf gene and determine the requirements for individual MEF2 family members in Bdnf regulation. MEF2A, MEF2C, and MEF2D are all highly expressed in embryonic rat cortical neurons; however, only the Mef2c gene encodes an MEF2 splice variant that lacks the γ repressor-domain. We find that MEF2C variants lacking the γ-domain are particularly sensitive to activation by membrane depolarization, raising the possibility that the MEF2s may differentially contribute to activity-regulated gene expression. We find that only knockdown of MEF2C significantly impairs membrane depolarization-induced expression of Bdnf exon IV. By contrast, knockdown of MEF2D significantly enhanced depolarization-induced expression of Bdnf exon I. Together, these data show that individual members of the MEF2 family of transcription factors differentially regulate the expression of Bdnf, revealing a new mechanism that may confer specificity on the induction of this biologically important gene.

Authors
Lyons, MR; Schwarz, CM; West, AE
MLA Citation
Lyons, MR, Schwarz, CM, and West, AE. "Members of the myocyte enhancer factor 2 transcription factor family differentially regulate Bdnf transcription in response to neuronal depolarization." The Journal of neuroscience : the official journal of the Society for Neuroscience 32.37 (September 2012): 12780-12785.
PMID
22973001
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
32
Issue
37
Publish Date
2012
Start Page
12780
End Page
12785
DOI
10.1523/jneurosci.0534-12.2012

Mutation of MeCP2 alters transcriptional regulation of select immediate-early genes.

Loss-of-function mutations in the methyl-DNA binding protein MeCP2 are associated with neurological dysfunction and impaired neural plasticity. However, the transcriptional changes that underlie these deficits remain poorly understood. Here, we show that mice bearing a C-terminal truncating mutation in Mecp2 (Mecp2 ( 308) ) are hypersensitive to the locomotor stimulating effects of cocaine. Furthermore, these mice have gene-specific alterations in striatal immediate-early gene (IEG) induction following cocaine administration. MeCP2 mutant mice show normal levels of baseline and cocaine-induced striatal Fos expression compared with their wild-type littermates. However, the mutant mice have enhanced cocaine-induced transcription of Junb and Arc. At the chromatin level, we find increased histone H3 acetylation at gene promoters in the Mecp2 mutant mice compared with their wild-type littermates, whereas two sites of repressive histone methylation are unchanged. Interestingly, we find that MeCP2 mutant mice show increased steady-state association of elongation-competent RNA Polymerase II (RNAP II) with the Junb and Arc promoters, whereas levels of RNAP II association at the Fos promoter are unchanged. These data reveal a gene-specific effect of MeCP2 on the recruitment of RNAP II to gene promoters that may modulate the inducibility of IEGs. In addition, our findings raise the possibility that aberrant regulation of IEGs including Junb and Arc may contribute to altered cocaine-induced neuronal and behavioral plasticity in Mecp2 mutant mice.

Authors
Su, D; Cha, YM; West, AE
MLA Citation
Su, D, Cha, YM, and West, AE. "Mutation of MeCP2 alters transcriptional regulation of select immediate-early genes." Epigenetics 7.2 (February 2012): 146-154.
PMID
22395464
Source
epmc
Published In
Epigenetics : official journal of the DNA Methylation Society
Volume
7
Issue
2
Publish Date
2012
Start Page
146
End Page
154
DOI
10.4161/epi.7.2.18907

Differential regulation of MeCP2 phosphorylation in the CNS by dopamine and serotonin.

Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional- and cell-type specificity of pMeCP2 induction. The D(1)-class DA receptor agonist SKF81297 induced pMeCP2 widely; however, coadministration of the D(2)-class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. Intra-striatal injection of the adenylate cyclase activator forskolin was sufficient to induce pMeCP2 in medium-spiny neurons, suggesting that the combinatorial regulation of cAMP by different classes of DA and 5-HT receptors may contribute to the cell-type specificity of pMeCP2 induction. Consistent with the regulation of pMeCP2 by multiple monoamine neurotransmitters, genetic disruption of any single monoamine transporter in DAT-, SERT-, and NET-knockout mice failed to eliminate AMPH-induced pMeCP2 in the NAc. Together, these studies indicate that combinatorial signaling through DA and 5-HT receptors can regulate the brain region- and cell-type specific pMeCP2 in the CNS.

Authors
Hutchinson, AN; Deng, JV; Aryal, DK; Wetsel, WC; West, AE
MLA Citation
Hutchinson, AN, Deng, JV, Aryal, DK, Wetsel, WC, and West, AE. "Differential regulation of MeCP2 phosphorylation in the CNS by dopamine and serotonin." Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 37.2 (January 2012): 321-337.
PMID
21956448
Source
epmc
Published In
Neuropsychopharmacology (Nature)
Volume
37
Issue
2
Publish Date
2012
Start Page
321
End Page
337
DOI
10.1038/npp.2011.190

Regulated shuttling of the histone deacetylase HDAC5 to the nucleus may put a brake on cocaine addiction.

The histone deacetylase HDAC5 has been shown to regulate behavioral adaptations to cocaine. In this issue of Neuron, Taniguchi et al. (2012) describe a cAMP-dependent signaling pathway that regulates nuclear accumulation of HDAC5, suggesting a mechanism to couple cocaine with changes in HDAC5 function.

Authors
West, AE
MLA Citation
West, AE. "Regulated shuttling of the histone deacetylase HDAC5 to the nucleus may put a brake on cocaine addiction." Neuron 73.1 (January 2012): 1-3.
PMID
22243740
Source
epmc
Published In
Neuron
Volume
73
Issue
1
Publish Date
2012
Start Page
1
End Page
3
DOI
10.1016/j.neuron.2011.12.016

Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function.

Autism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation in vivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitate a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling.

Authors
Cohen, S; Gabel, HW; Hemberg, M; Hutchinson, AN; Sadacca, LA; Ebert, DH; Harmin, DA; Greenberg, RS; Verdine, VK; Zhou, Z; Wetsel, WC; West, AE; Greenberg, ME
MLA Citation
Cohen, S, Gabel, HW, Hemberg, M, Hutchinson, AN, Sadacca, LA, Ebert, DH, Harmin, DA, Greenberg, RS, Verdine, VK, Zhou, Z, Wetsel, WC, West, AE, and Greenberg, ME. "Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function." Neuron 72.1 (October 2011): 72-85.
PMID
21982370
Source
epmc
Published In
Neuron
Volume
72
Issue
1
Publish Date
2011
Start Page
72
End Page
85
DOI
10.1016/j.neuron.2011.08.022

Mechanisms of specificity in neuronal activity-regulated gene transcription.

The brain is a highly adaptable organ that is capable of converting sensory information into changes in neuronal function. This plasticity allows behavior to be accommodated to the environment, providing an important evolutionary advantage. Neurons convert environmental stimuli into long-lasting changes in their physiology in part through the synaptic activity-regulated transcription of new gene products. Since the neurotransmitter-dependent regulation of Fos transcription was first discovered nearly 25 years ago, a wealth of studies have enriched our understanding of the molecular pathways that mediate activity-regulated changes in gene transcription. These findings show that a broad range of signaling pathways and transcriptional regulators can be engaged by neuronal activity to sculpt complex programs of stimulus-regulated gene transcription. However, the shear scope of the transcriptional pathways engaged by neuronal activity raises the question of how specificity in the nature of the transcriptional response is achieved in order to encode physiologically relevant responses to divergent stimuli. Here we summarize the general paradigms by which neuronal activity regulates transcription while focusing on the molecular mechanisms that confer differential stimulus-, cell-type-, and developmental-specificity upon activity-regulated programs of neuronal gene transcription. In addition, we preview some of the new technologies that will advance our future understanding of the mechanisms and consequences of activity-regulated gene transcription in the brain.

Authors
Lyons, MR; West, AE
MLA Citation
Lyons, MR, and West, AE. "Mechanisms of specificity in neuronal activity-regulated gene transcription." Progress in neurobiology 94.3 (August 2011): 259-295. (Review)
Website
http://hdl.handle.net/10161/5425
PMID
21620929
Source
epmc
Published In
Progress in Neurobiology
Volume
94
Issue
3
Publish Date
2011
Start Page
259
End Page
295
DOI
10.1016/j.pneurobio.2011.05.003

Neuronal activity-regulated gene transcription in synapse development and cognitive function.

Activity-dependent plasticity of vertebrate neurons allows the brain to respond to its environment. During brain development, both spontaneous and sensory-driven neural activity are essential for instructively guiding the process of synapse development. These effects of neuronal activity are transduced in part through the concerted regulation of a set of activity-dependent transcription factors that coordinate a program of gene expression required for the formation and maturation of synapses. Here we review the cellular signaling networks that regulate the activity of transcription factors during brain development and discuss the functional roles of specific activity-regulated transcription factors in specific stages of synapse formation, refinement, and maturation. Interestingly, a number of neurodevelopmental disorders have been linked to abnormalities in activity-regulated transcriptional pathways, indicating that these signaling networks are critical for cognitive development and function.

Authors
West, AE; Greenberg, ME
MLA Citation
West, AE, and Greenberg, ME. "Neuronal activity-regulated gene transcription in synapse development and cognitive function." Cold Spring Harbor perspectives in biology 3.6 (June 2011). (Review)
PMID
21555405
Source
epmc
Published In
Cold Spring Harbor perspectives in biology
Volume
3
Issue
6
Publish Date
2011
DOI
10.1101/cshperspect.a005744

Biological functions and transcriptional targets of CaRF in neurons.

Calcium-response factor (CaRF) is a unique DNA-binding protein first recognized as a transcription factor for its role in modulating transcription of the gene encoding Brain-Derived Neurotrophic Factor (BDNF) in neurons. Here I review evidence for the biological functions and transcriptional targets of CaRF in the brain and discuss potential mechanisms by which calcium-activated signaling pathways may modulate CaRF-dependent transcription. These data paint an emerging picture of CaRF as a regulatory nexus for signaling pathways that control aspects of synaptic development and neuronal function.

Authors
West, AE
MLA Citation
West, AE. "Biological functions and transcriptional targets of CaRF in neurons." Cell calcium 49.5 (May 11, 2011): 290-295. (Review)
PMID
21565403
Source
epmc
Published In
Cell Calcium
Volume
49
Issue
5
Publish Date
2011
Start Page
290
End Page
295
DOI
10.1016/j.ceca.2011.04.003

MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants.

MeCP2 is a methyl DNA-binding transcriptional regulator that contributes to the development and function of CNS synapses; however, the requirement for MeCP2 in stimulus-regulated behavioral plasticity is not fully understood. Here we show that acute viral manipulation of MeCP2 expression in the nucleus accumbens (NAc) bidirectionally modulates amphetamine (AMPH)-induced conditioned place preference. Mecp2 hypomorphic mutant mice have more NAc GABAergic synapses and show deficient AMPH-induced structural plasticity of NAc dendritic spines. Furthermore, these mice show deficient plasticity of striatal immediate early gene inducibility after repeated AMPH administration. Notably, psychostimulants induce phosphorylation of MeCP2 at Ser421, a site that regulates MeCP2's function as a repressor. Phosphorylation is selectively induced in GABAergic interneurons of the NAc, and its extent strongly predicts the degree of behavioral sensitization. These data reveal new roles for MeCP2 both in mesolimbocortical circuit development and in the regulation of psychostimulant-induced behaviors.

Authors
Deng, JV; Rodriguiz, RM; Hutchinson, AN; Kim, I-H; Wetsel, WC; West, AE
MLA Citation
Deng, JV, Rodriguiz, RM, Hutchinson, AN, Kim, I-H, Wetsel, WC, and West, AE. "MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants." Nature neuroscience 13.9 (September 2010): 1128-1136.
PMID
20711186
Source
epmc
Published In
Nature Neuroscience
Volume
13
Issue
9
Publish Date
2010
Start Page
1128
End Page
1136
DOI
10.1038/nn.2614

Reduced cortical BDNF expression and aberrant memory in Carf knock-out mice.

Transcription factors are a key point of convergence between the cell-intrinsic and extracellular signals that guide synaptic development and brain plasticity. Calcium-response factor (CaRF) is a unique transcription factor first identified as a binding protein for a calcium-response element in the gene encoding brain-derived neurotrophic factor (Bdnf). We have now generated Carf knock-out (KO) mice to characterize the function of this factor in vivo. Intriguingly, Carf KO mice have selectively reduced expression of Bdnf exon IV-containing mRNA transcripts and BDNF protein in the cerebral cortex, whereas BDNF levels in the hippocampus and striatum remain unchanged, implicating CaRF as a brain region-selective regulator of BDNF expression. At the cellular level, Carf KO mice show altered expression of GABAergic proteins at striatal synapses, raising the possibility that CaRF may contribute to aspects of inhibitory synapse development. Carf KO mice show normal spatial learning in the Morris water maze and normal context-dependent fear conditioning. However they have an enhanced ability to find a new platform location on the first day of reversal training in the water maze and they extinguish conditioned fear more slowly than their wild-type littermates. Finally, Carf KO mice show normal short-term (STM) and long-term memory (LTM) in a novel object recognition task, but exhibit impairments during the remote memory phase of testing. Together, these data reveal novel roles for CaRF in the organization and/or function of neural circuits that underlie essential aspects of learning and memory.

Authors
McDowell, KA; Hutchinson, AN; Wong-Goodrich, SJE; Presby, MM; Su, D; Rodriguiz, RM; Law, KC; Williams, CL; Wetsel, WC; West, AE
MLA Citation
McDowell, KA, Hutchinson, AN, Wong-Goodrich, SJE, Presby, MM, Su, D, Rodriguiz, RM, Law, KC, Williams, CL, Wetsel, WC, and West, AE. "Reduced cortical BDNF expression and aberrant memory in Carf knock-out mice." The Journal of neuroscience : the official journal of the Society for Neuroscience 30.22 (June 2010): 7453-7465.
PMID
20519520
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
30
Issue
22
Publish Date
2010
Start Page
7453
End Page
7465
DOI
10.1523/jneurosci.3997-09.2010

Genome-wide identification of calcium-response factor (CaRF) binding sites predicts a role in regulation of neuronal signaling pathways.

Calcium-Response Factor (CaRF) was first identified as a transcription factor based on its affinity for a neuronal-selective calcium-response element (CaRE1) in the gene encoding Brain-Derived Neurotrophic Factor (BDNF). However, because CaRF shares no homology with other transcription factors, its properties and gene targets have remained unknown. Here we show that the DNA binding domain of CaRF has been highly conserved across evolution and that CaRF binds DNA directly in a sequence-specific manner in the absence of other eukaryotic cofactors. Using a binding site selection screen we identify a high-affinity consensus CaRF response element (cCaRE) that shares significant homology with the CaRE1 element of Bdnf. In a genome-wide chromatin immunoprecipitation analysis (ChIP-Seq), we identified 176 sites of CaRF-specific binding (peaks) in neuronal genomic DNA. 128 of these peaks are within 10kB of an annotated gene, and 60 are within 1kB of an annotated transcriptional start site. At least 138 of the CaRF peaks contain a common 10-bp motif with strong statistical similarity to the cCaRE, and we provide evidence predicting that CaRF can bind independently to at least 64.5% of these motifs in vitro. Analysis of this set of putative CaRF targets suggests the enrichment of genes that regulate intracellular signaling cascades. Finally we demonstrate that expression of a subset of these target genes is altered in the cortex of Carf knockout (KO) mice. Together these data strongly support the characterization of CaRF as a unique transcription factor and provide the first insight into the program of CaRF-regulated transcription in neurons.

Authors
Pfenning, AR; Kim, T-K; Spotts, JM; Hemberg, M; Su, D; West, AE
MLA Citation
Pfenning, AR, Kim, T-K, Spotts, JM, Hemberg, M, Su, D, and West, AE. "Genome-wide identification of calcium-response factor (CaRF) binding sites predicts a role in regulation of neuronal signaling pathways." PloS one 5.5 (May 27, 2010): e10870-.
PMID
20523734
Source
epmc
Published In
PloS one
Volume
5
Issue
5
Publish Date
2010
Start Page
e10870
DOI
10.1371/journal.pone.0010870

Genome-wide identification of calcium-response factor (CaRF) binding sites predicts a role in regulation of neuronal signaling pathways

Calcium-Response Factor (CaRF) was first identified as a transcription factor based on its affinity for a neuronal-selective calcium-response element (CaRE1) in the gene encoding Brain-Derived Neurotrophic Factor (BDNF). However, because CaRF shares no homology with other transcription factors, its properties and gene targets have remained unknown. Here we show that the DNA binding domain of CaRF has been highly conserved across evolution and that CaRF binds DNA directly in a sequence-specific manner in the absence of other eukaryotic cofactors. Using a binding site selection screen we identify a high-affinity consensus CaRF response element (cCaRE) that shares significant homology with the CaRE1 element of Bdnf. In a genome-wide chromatin immunoprecipitation analysis (ChIP-Seq), we identified 176 sites of CaRF-specific binding (peaks) in neuronal genomic DNA. 128 of these peaks are within 10kB of an annotated gene, and 60 are within 1kB of an annotated transcriptional start site. At least 138 of the CaRF peaks contain a common 10-bp motif with strong statistical similarity to the cCaRE, and we provide evidence predicting that CaRF can bind independently to at least 64.5% of these motifs in vitro. Analysis of this set of putative CaRF targets suggests the enrichment of genes that regulate intracellular signaling cascades. Finally we demonstrate that expression of a subset of these target genes is altered in the cortex of Carf knockout (KO) mice. Together these data strongly support the characterization of CaRF as a unique transcription factor and provide the first insight into the program of CaRF-regulated transcription in neurons. © 2010 Pfenning et al.

Authors
Pfenning, AR; Kim, T-K; Spotts, JM; Hemberg, M; Su, D; West, AE
MLA Citation
Pfenning, AR, Kim, T-K, Spotts, JM, Hemberg, M, Su, D, and West, AE. "Genome-wide identification of calcium-response factor (CaRF) binding sites predicts a role in regulation of neuronal signaling pathways." PLoS ONE 5.5 (2010).
Website
http://hdl.handle.net/10161/4544
Source
scival
Published In
PloS one
Volume
5
Issue
5
Publish Date
2010
DOI
10.1371/journal.pone.0010870

BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV.

The Ca(2+)/calmodulin-activated kinases CaMKK2 and CaMKIV are highly expressed in the brain where they play important roles in activating intracellular responses to elevated Ca(2+). To address the biological functions of Ca(2+) signaling via these kinases during brain development, we have examined cerebellar development in mice null for CaMKK2 or CaMKIV. Here, we demonstrate that CaMKK2/CaMKIV-dependent phosphorylation of cAMP response element-binding protein (CREB) correlates with Bdnf transcription, which is required for normal development of cerebellar granule cell neurons. We show in vivo and in vitro that the absence of either CaMKK2 or CaMKIV disrupts the ability of developing cerebellar granule cells in the external granule cell layer to cease proliferation and begin migration to the internal granule cell layer. Furthermore, loss of CaMKK2 or CaMKIV results in decreased CREB phosphorylation (pCREB), Bdnf exon I and IV-containing mRNAs, and brain-derived neurotrophic factor (BDNF) protein in cerebellar granule cell neurons. Reexpression of CaMKK2 or CaMKIV in granule cells that lack CaMKK2 or CaMKIV, respectively, restores pCREB and BDNF to wild-type levels and addition of BDNF rescues granule cell migration in vitro. These results reveal a previously undefined role for a CaMKK2/CaMKIV cascade involved in cerebellar granule cell development and show specifically that Ca(2+)-dependent regulation of BDNF through CaMKK2/CaMKIV is required for this process.

Authors
Kokubo, M; Nishio, M; Ribar, TJ; Anderson, KA; West, AE; Means, AR
MLA Citation
Kokubo, M, Nishio, M, Ribar, TJ, Anderson, KA, West, AE, and Means, AR. "BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV." J Neurosci 29.28 (July 15, 2009): 8901-8913.
PMID
19605628
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
29
Issue
28
Publish Date
2009
Start Page
8901
End Page
8913
DOI
10.1523/JNEUROSCI.0040-09.2009

Biological functions of activity-dependent transcription revealed.

Neuronal activity regulates the transcription of a large set of genes, many of which encode proteins that modify synaptic function. In this issue of Neuron, Hong et al. selectively impair activity-dependent Bdnf transcription and demonstrate that this process is required for inhibitory synapse development.

Authors
West, AE
MLA Citation
West, AE. "Biological functions of activity-dependent transcription revealed." Neuron 60.4 (November 2008): 523-525. (Review)
PMID
19038208
Source
epmc
Published In
Neuron
Volume
60
Issue
4
Publish Date
2008
Start Page
523
End Page
525
DOI
10.1016/j.neuron.2008.11.008

Activity-dependent regulation of Brain-derived neurotrophic factor transcription

Authors
West, AE
MLA Citation
West, AE. "Activity-dependent regulation of Brain-derived neurotrophic factor transcription." TRANSCRIPTIONAL REGULATION BY NEURONAL ACTIVITY (2008): 155-173.
Source
wos-lite
Published In
TRANSCRIPTIONAL REGULATION BY NEURONAL ACTIVITY
Publish Date
2008
Start Page
155
End Page
173
DOI
10.1007/978-0-387-73609-9_8

Differential regulation of c-jun and CREB by acrolein and 4-hydroxynonenal

In Alzheimer's disease (AD), oxidative stress-induced lipid peroxidation leads to accumulation of unsaturated aldehydes including acrolein and 4-hydroxynonenal (4HNE) in brain. In this study, we examined the effects of these lipid peroxidation products on apoptotic pathways in cultured neurons. Acrolein and 4HNE increased the levels of active phosphorylated forms of c-jun and CREB, the transcription factors that promote apoptosis and cell survival, respectively. However, they decreased the activity of CREB-dependent BDNF promoter while they increased the activity of promoters responsive to c-jun. We hypothesized that this differential regulation could be due to competition between proapoptotic c-jun and cytoprotective CREB for CBP (CREB-binding protein), a coactivator shared by several transcription factors. In support of this hypothesis, we demonstrate that the decrease of BDNF promoter activity by acrolein and 4HNE could be restored (i) by cotransfection with CBP, (ii) by cotransfection with VP 16-CREB, a constitutively active form of CREB that does not depend on CBP for its activation, or (iii) by inhibiting JNK-mediated c-jun activation. Finally, adenoviral transduction of hippocampal neurons with VP 16-CREB resulted in significant reduction in caspase-3 activation by acrolein and 4HNE. These observations suggest that lipid peroxidation-induced differential regulation of CREB and c-jun might play a role in neurodegeneration in AD. © 2005 Elsevier Inc. All rights reserved.

Authors
Pugazhenthi, S; Phansalkar, K; Audesirk, G; West, A; Cabell, L
MLA Citation
Pugazhenthi, S, Phansalkar, K, Audesirk, G, West, A, and Cabell, L. "Differential regulation of c-jun and CREB by acrolein and 4-hydroxynonenal." Free Radical Biology and Medicine 40.1 (2006): 21-34.
PMID
16337876
Source
scival
Published In
Free Radical Biology & Medicine
Volume
40
Issue
1
Publish Date
2006
Start Page
21
End Page
34
DOI
10.1016/j.freeradbiomed.2005.08.023

Transcriptional control of cognitive development.

Cognitive development is determined by both genetics and environment. One point of convergence of these two influences is the neural activity-dependent regulation of programs of gene expression that specify neuronal fate and function. Human genetic studies have linked several transcriptional regulators to neurodevelopmental disorders including mental retardation and autism spectrum disorders. Recent reports on two such factors, CREB-binding protein and methyl-CpG-binding protein 2, have begun to reveal how epigenetics and neuronal activity act to modulate the program of gene expression required for synaptic development and function.

Authors
Hong, EJ; West, AE; Greenberg, ME
MLA Citation
Hong, EJ, West, AE, and Greenberg, ME. "Transcriptional control of cognitive development." Current opinion in neurobiology 15.1 (February 2005): 21-28. (Review)
PMID
15721740
Source
epmc
Published In
Current Opinion in Neurobiology
Volume
15
Issue
1
Publish Date
2005
Start Page
21
End Page
28
DOI
10.1016/j.conb.2005.01.002

Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2.

Mutations in MeCP2, which encodes a protein that has been proposed to function as a global transcriptional repressor, are the cause of Rett syndrome (RT T), an X-linked progressive neurological disorder. Although the selective inactivation of MeCP2 in neurons is sufficient to confer a Rett-like phenotype in mice, the specific functions of MeCP2 in postmitotic neurons are not known. We find that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene. Membrane depolarization triggers the calcium-dependent phosphorylation and release of MeCP2 from BDNF promoter III, thereby facilitating transcription. These studies indicate that MeCP2 plays a key role in the control of neuronal activity-dependent gene regulation and suggest that the deregulation of this process may underlie the pathology of RT T.

Authors
Chen, WG; Chang, Q; Lin, Y; Meissner, A; West, AE; Griffith, EC; Jaenisch, R; Greenberg, ME
MLA Citation
Chen, WG, Chang, Q, Lin, Y, Meissner, A, West, AE, Griffith, EC, Jaenisch, R, and Greenberg, ME. "Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2." Science (New York, N.Y.) 302.5646 (October 2003): 885-889.
PMID
14593183
Source
epmc
Published In
Science
Volume
302
Issue
5646
Publish Date
2003
Start Page
885
End Page
889
DOI
10.1126/science.1086446

Upstream stimulatory factors are mediators of Ca2+-responsive transcription in neurons.

To identify molecular mechanisms that control activity-dependent gene expression in the CNS, we have characterized the factors that mediate activity-dependent transcription of BDNF promoter III. We report the identification of a Ca(2+)-responsive E-box element, CaRE2, within BDNF promoter III that binds upstream stimulatory factors 1 and 2 (USF1/2) and show that USFs are required for the activation of CaRE2-dependent transcription from BDNF promoter III. We find that the transcriptional activity of the USFs is regulated by Ca(2+)-activated signaling pathways in neurons and that the USFs bind to the promoters of a number of neuronal activity-regulated genes in vivo. These results suggest a new function for the USFs in the regulation of activity-dependent transcription in neurons.

Authors
Chen, WG; West, AE; Tao, X; Corfas, G; Szentirmay, MN; Sawadogo, M; Vinson, C; Greenberg, ME
MLA Citation
Chen, WG, West, AE, Tao, X, Corfas, G, Szentirmay, MN, Sawadogo, M, Vinson, C, and Greenberg, ME. "Upstream stimulatory factors are mediators of Ca2+-responsive transcription in neurons." The Journal of neuroscience : the official journal of the Society for Neuroscience 23.7 (April 2003): 2572-2581.
PMID
12684442
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
23
Issue
7
Publish Date
2003
Start Page
2572
End Page
2581

Regulation of transcription factors by neuronal activity.

Authors
West, AE; Griffith, EC; Greenberg, ME
MLA Citation
West, AE, Griffith, EC, and Greenberg, ME. "Regulation of transcription factors by neuronal activity." Nature reviews. Neuroscience 3.12 (December 2002): 921-931. (Review)
PMID
12461549
Source
epmc
Published In
Nature Reviews Neuroscience
Volume
3
Issue
12
Publish Date
2002
Start Page
921
End Page
931
DOI
10.1038/nrn987

A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF.

Transcription of the brain-derived neurotrophic factor (BDNF) gene is regulated in a calcium- and neuron-selective manner; however, the mechanisms that underlie this selectivity are not known. We have characterized a new calcium-response element, CaRE1, that is required for activity-dependent transcription of BDNF exon III and have cloned a transcription factor, CaRF, that activates transcription from BDNF promoter III in a CaRE1-dependent manner. The transcriptional activity of CaRF is regulated in a calcium- and neuron-selective manner, suggesting that CaRF may confer selectivity upon the activity-dependent induction of BDNF exon III expression.

Authors
Tao, X; West, AE; Chen, WG; Corfas, G; Greenberg, ME
MLA Citation
Tao, X, West, AE, Chen, WG, Corfas, G, and Greenberg, ME. "A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF." Neuron 33.3 (January 2002): 383-395.
PMID
11832226
Source
epmc
Published In
Neuron
Volume
33
Issue
3
Publish Date
2002
Start Page
383
End Page
395
DOI
10.1016/s0896-6273(01)00561-x

Calcium regulation of neuronal gene expression.

Plasticity is a remarkable feature of the brain, allowing neuronal structure and function to accommodate to patterns of electrical activity. One component of these long-term changes is the activity-driven induction of new gene expression, which is required for both the long-lasting long-term potentiation of synaptic transmission associated with learning and memory, and the activity dependent survival events that help to shape and wire the brain during development. We have characterized molecular mechanisms by which neuronal membrane depolarization and subsequent calcium influx into the cytoplasm lead to the induction of new gene transcription. We have identified three points within this cascade of events where the specificity of genes induced by different types of stimuli can be regulated. By using the induction of the gene that encodes brain-derived neurotrophic factor (BDNF) as a model, we have found that the ability of a calcium influx to induce transcription of this gene is regulated by the route of calcium entry into the cell, by the pattern of phosphorylation induced on the transcription factor cAMP-response element (CRE) binding protein (CREB), and by the complement of active transcription factors recruited to the BDNF promoter. These results refine and expand the working model of activity-induced gene induction in the brain, and help to explain how different types of neuronal stimuli can activate distinct transcriptional responses.

Authors
West, AE; Chen, WG; Dalva, MB; Dolmetsch, RE; Kornhauser, JM; Shaywitz, AJ; Takasu, MA; Tao, X; Greenberg, ME
MLA Citation
West, AE, Chen, WG, Dalva, MB, Dolmetsch, RE, Kornhauser, JM, Shaywitz, AJ, Takasu, MA, Tao, X, and Greenberg, ME. "Calcium regulation of neuronal gene expression." Proceedings of the National Academy of Sciences of the United States of America 98.20 (September 2001): 11024-11031. (Review)
PMID
11572963
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
98
Issue
20
Publish Date
2001
Start Page
11024
End Page
11031
DOI
10.1073/pnas.191352298

Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms.

A mechanism by which the Ras-mitogen-activated protein kinase (MAPK) signaling pathway mediates growth factor-dependent cell survival was characterized. The MAPK-activated kinases, the Rsks, catalyzed the phosphorylation of the pro-apoptotic protein BAD at serine 112 both in vitro and in vivo. The Rsk-induced phosphorylation of BAD at serine 112 suppressed BAD-mediated apoptosis in neurons. Rsks also are known to phosphorylate the transcription factor CREB (cAMP response element-binding protein) at serine 133. Activated CREB promoted cell survival, and inhibition of CREB phosphorylation at serine 133 triggered apoptosis. These findings suggest that the MAPK signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of pro-survival genes.

Authors
Bonni, A; Brunet, A; West, AE; Datta, SR; Takasu, MA; Greenberg, ME
MLA Citation
Bonni, A, Brunet, A, West, AE, Datta, SR, Takasu, MA, and Greenberg, ME. "Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms." Science (New York, N.Y.) 286.5443 (November 1999): 1358-1362.
PMID
10558990
Source
epmc
Published In
Science
Volume
286
Issue
5443
Publish Date
1999
Start Page
1358
End Page
1362
DOI
10.1126/science.286.5443.1358

Protein targeting in neurons and endocrine cells.

Authors
West, AE; Provoda, C; Neve, RL; Buckley, KM
MLA Citation
West, AE, Provoda, C, Neve, RL, and Buckley, KM. "Protein targeting in neurons and endocrine cells." Advances in pharmacology (San Diego, Calif.) 42 (January 1998): 247-249.
PMID
9327890
Source
epmc
Published In
Advances in pharmacology (San Diego, Calif.)
Volume
42
Publish Date
1998
Start Page
247
End Page
249

Protein targeting in neurons and endocrine cells.

Authors
West, AE; Provoda, C; Neve, RL; Buckley, KM
MLA Citation
West, AE, Provoda, C, Neve, RL, and Buckley, KM. "Protein targeting in neurons and endocrine cells." Advances in pharmacology (San Diego, Calif.) 42 (1998): 247-249.
Source
scival
Published In
Advances in pharmacology (San Diego, Calif.)
Volume
42
Publish Date
1998
Start Page
247
End Page
249

Targeting of the synaptic vesicle protein synaptobrevin in the axon of cultured hippocampal neurons: evidence for two distinct sorting steps.

Synaptic vesicles are concentrated in the distal axon, far from the site of protein synthesis. Integral membrane proteins destined for this organelle must therefore make complex targeting decisions. Short amino acid sequences have been shown to act as targeting signals directing proteins to a variety of intracellular locations. To identify synaptic vesicle targeting sequences and to follow the path that proteins travel en route to the synaptic vesicle, we have used a defective herpes virus amplicon expression system to study the targeting of a synaptobrevin-transferrin receptor (SB-TfR) chimera in cultured hippocampal neurons. Addition of the cytoplasmic domain of synaptobrevin onto human transferrin receptor was sufficient to retarget the transferrin receptor from the dendrites to presynaptic sites in the axon. At the synapse, the SB-TfR chimera did not localize to synaptic vesicles, but was instead found in an organelle with biochemical and functional characteristics of an endosome. The chimera recycled in parallel with synaptic vesicle proteins demonstrating that the nerve terminal efficiently sorts transmembrane proteins into different pathways. The synaptobrevin sequence that controls targeting to the presynaptic endosome was not localized to a single, 10- amino acid region of the molecule, indicating that this targeting signal may be encoded by a more distributed structural conformation. However, the chimera could be shifted to synaptic vesicles by deletion of amino acids 61-70 in synaptobrevin, suggesting that separate signals encode the localization of synaptobrevin to the synapse and to the synaptic vesicle.

Authors
West, AE; Neve, RL; Buckley, KM
MLA Citation
West, AE, Neve, RL, and Buckley, KM. "Targeting of the synaptic vesicle protein synaptobrevin in the axon of cultured hippocampal neurons: evidence for two distinct sorting steps." The Journal of cell biology 139.4 (November 1997): 917-927.
PMID
9362510
Source
epmc
Published In
The Journal of Cell Biology
Volume
139
Issue
4
Publish Date
1997
Start Page
917
End Page
927
DOI
10.1083/jcb.139.4.917

Identification of a somatodendritic targeting signal in the cytoplasmic domain of the transferrin receptor.

Neurons are highly polarized cells that must sort proteins synthesized in the cell body for transport into the axon or the dendrites. Given the amount of time and energy needed to deliver proteins to the distal processes, neurons must have high fidelity mechanisms that ensure proper polarized protein trafficking. Although a variety of proteins are localized either to the somatodendritic domain or to the axon (), the question of whether there are signal-dependent mechanisms that sort proteins to distinct neuronal domains is only beginning to be addressed. To determine sequence requirements for the polarized sorting of transmembrane proteins into dendrites, we expressed mutant transferrin receptors in cultured rat hippocampal neurons, using a defective herpes virus vector. Wild-type human transferrin receptor colocalized with the endogenous protein in dendritic endosomes and was strictly excluded from axons, despite overexpression. Polarized targeting was abolished by deletion of cytoplasmic amino acids 7-10, 11-14, or 19-28, but not 29-42 or 43-58. These deletions also increased the appearance of transferrin receptor on the plasma membrane, implying that endocytosis and dendritic targeting are mediated by overlapping signals and similar molecular mechanisms. In addition, we have characterized a specialized para-Golgi endosome poised to play a critical role in the polarized recycling of transmembrane proteins.

Authors
West, AE; Neve, RL; Buckley, KM
MLA Citation
West, AE, Neve, RL, and Buckley, KM. "Identification of a somatodendritic targeting signal in the cytoplasmic domain of the transferrin receptor." The Journal of neuroscience : the official journal of the Society for Neuroscience 17.16 (August 1997): 6038-6047.
PMID
9236215
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
17
Issue
16
Publish Date
1997
Start Page
6038
End Page
6047
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