Anne West

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:

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

Cornell University

M.D. 1998

Harvard University

Ph.D. 1998

Harvard University

Grants:

Training Program in Developmental and Stem Cell Biology

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

IRES Track 1 IRTG Engaged in Dissecting and Reengineering the Regulatory Genome

Administered By
Duke Center for Applied Genomics and Precision Medicine
Awarded By
National Science Foundation
Role
Mentor
Start Date
End Date

Behavioral and Synaptic Consequences of MeCP2 Phosphorylation

Administered By
Neurobiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

In Vivo Epigenome Editing with CRISPR-Based Histone Acetyltransferase Transgenic Mice

Administered By
Neurobiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Epigenome Editing Technologies to Control Diverse Biological Functions

Administered By
Biomedical Engineering
Awarded By
Allen Institute for Brain Science
Role
Co Investigator
Start Date
End Date

Publications:

Transgenic mice for in vivo epigenome editing with CRISPR-based systems.

CRISPR-Cas9 technologies have dramatically increased the ease of targeting DNA sequences in the genomes of living systems. The fusion of chromatin-modifying domains to nuclease-deactivated Cas9 (dCas9) has enabled targeted epigenome editing in both cultured cells and animal models. However, delivering large dCas9 fusion proteins to target cells and tissues is an obstacle to the widespread adoption of these tools for in vivo studies. Here, we describe the generation and characterization of two conditional transgenic mouse lines for epigenome editing, Rosa26:LSL-dCas9-p300 for gene activation and Rosa26:LSL-dCas9-KRAB for gene repression. By targeting the guide RNAs to transcriptional start sites or distal enhancer elements, we demonstrate regulation of target genes and corresponding changes to epigenetic states and downstream phenotypes in the brain and liver in vivo, and in T cells and fibroblasts ex vivo. These mouse lines are convenient and valuable tools for facile, temporally controlled, and tissue-restricted epigenome editing and manipulation of gene expression in vivo.
Authors
Gemberling, MP; Siklenka, K; Rodriguez, E; Tonn-Eisinger, KR; Barrera, A; Liu, F; Kantor, A; Li, L; Cigliola, V; Hazlett, MF; Williams, CA; Bartelt, LC; Madigan, VJ; Bodle, JC; Daniels, H; Rouse, DC; Hilton, IB; Asokan, A; Ciofani, M; Poss, KD; Reddy, TE; West, AE; Gersbach, CA
MLA Citation
Gemberling, Matthew P., et al. “Transgenic mice for in vivo epigenome editing with CRISPR-based systems.Nat Methods, vol. 18, no. 8, Aug. 2021, pp. 965–74. Pubmed, doi:10.1038/s41592-021-01207-2.
URI
https://scholars.duke.edu/individual/pub1492755
PMID
34341582
Source
pubmed
Published In
Nat Methods
Volume
18
Published Date
Start Page
965
End Page
974
DOI
10.1038/s41592-021-01207-2

Utilizing In Vivo Postnatal Electroporation to Study Cerebellar Granule Neuron Morphology and Synapse Development.

Neurons undergo dynamic changes in their structure and function during brain development to form appropriate connections with other cells. The rodent cerebellum is an ideal system to track the development and morphogenesis of a single cell type, the cerebellar granule neuron (CGN), across time. Here, in vivo electroporation of granule neuron progenitors in the developing mouse cerebellum was employed to sparsely label cells for subsequent morphological analyses. The efficacy of this technique is demonstrated in its ability to showcase key developmental stages of CGN maturation, with a specific focus on the formation of dendritic claws, which are specialized structures where these cells receive the majority of their synaptic inputs. In addition to providing snapshots of CGN synaptic structures throughout cerebellar development, this technique can be adapted to genetically manipulate granule neurons in a cell-autonomous manner to study the role of any gene of interest and its effect on CGN morphology, claw development, and synaptogenesis.
Authors
Chan, U; Gautam, D; West, AE
MLA Citation
Chan, Urann, et al. “Utilizing In Vivo Postnatal Electroporation to Study Cerebellar Granule Neuron Morphology and Synapse Development.J Vis Exp, no. 172, June 2021. Pubmed, doi:10.3791/62568.
URI
https://scholars.duke.edu/individual/pub1487760
PMID
34180898
Source
pubmed
Published In
Journal of Visualized Experiments : Jove
Published Date
DOI
10.3791/62568

TRPing into excitotoxic neuronal death.

It is a striking paradox that the activation of NMDA-type glutamate receptors (NMDARs) can both promote neuronal survival and induce excitotoxic cell death. Yet the molecular mechanisms that distinguish these cellular consequences have remained obscure. A recent study by Yan et al. (2020) reveals a novel interaction between NMDARs and TRPM4 that is required for NMDAR-induced neuronal death. Small molecule disruption of this interaction reduces excitotoxicity in stroke without blocking physiological NMDAR signaling.
Authors
Green, MV; West, AE
MLA Citation
Green, Matthew V., and Anne E. West. “TRPing into excitotoxic neuronal death.Cell Calcium, vol. 93, Jan. 2021, p. 102331. Pubmed, doi:10.1016/j.ceca.2020.102331.
URI
https://scholars.duke.edu/individual/pub1469235
PMID
33341523
Source
pubmed
Published In
Cell Calcium
Volume
93
Published Date
Start Page
102331
DOI
10.1016/j.ceca.2020.102331

The NMDA receptor subunit GluN3A regulates synaptic activity-induced and myocyte enhancer factor 2C (MEF2C)-dependent transcription.

N-Methyl-d-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the glutamate receptor ionotropic NMDA 2 (GluN2) subunit composition of NMDARs determines whether they activate the transcription factor cAMP-responsive element-binding protein 1 (CREB). However, whether the developmentally regulated GluN3A subunit also modulates NMDAR-induced transcription is unknown. Here, using an array of techniques, including quantitative real-time PCR, immunostaining, reporter gene assays, RNA-Seq, and two-photon glutamate uncaging with calcium imaging, we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. We found that this enhancement is mediated by the accumulation of phosphorylated p38 mitogen-activated protein kinase in the nucleus, which drives the activation of the transcription factor myocyte enhancer factor 2C (MEF2C) and promotes the transcription of a subset of synaptic activity-induced genes, including brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton-associated protein (Arc). Our evidence that GluN3A regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity to the program of synaptic activity-regulated gene transcription in developing neurons.
Authors
Chen, L-F; Lyons, MR; Liu, F; Green, MV; Hedrick, NG; Williams, AB; Narayanan, A; Yasuda, R; West, AE
MLA Citation
Chen, Liang-Fu, et al. “The NMDA receptor subunit GluN3A regulates synaptic activity-induced and myocyte enhancer factor 2C (MEF2C)-dependent transcription.J Biol Chem, vol. 295, no. 25, June 2020, pp. 8613–27. Pubmed, doi:10.1074/jbc.RA119.010266.
URI
https://scholars.duke.edu/individual/pub1441635
PMID
32393578
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
295
Published Date
Start Page
8613
End Page
8627
DOI
10.1074/jbc.RA119.010266

Neurobiological functions of transcriptional enhancers.

Transcriptional enhancers are regulatory DNA elements that underlie the specificity and dynamic patterns of gene expression. Over the past decade, large-scale functional genomics projects have driven transformative progress in our understanding of enhancers. These data have relevance for identifying mechanisms of gene regulation in the CNS, elucidating the function of non-coding regulatory sequences in neurobiology and linking sequence variation within enhancers to genetic risk for neurological and psychiatric disorders. However, the sheer volume and complexity of genomic data presents a challenge to interpreting enhancer function in normal and pathogenic neurobiological processes. Here, to advance the application of genome-scale enhancer data, we offer a primer on current models of enhancer function in the CNS, we review how enhancers regulate gene expression across the neuronal lifespan, and we suggest how emerging findings regarding the role of non-coding sequence variation offer opportunities for understanding brain disorders and developing new technologies for neuroscience.
Authors
Nord, AS; West, AE
MLA Citation
Nord, Alex S., and Anne E. West. “Neurobiological functions of transcriptional enhancers.Nat Neurosci, vol. 23, no. 1, Jan. 2020, pp. 5–14. Pubmed, doi:10.1038/s41593-019-0538-5.
URI
https://scholars.duke.edu/individual/pub1421528
PMID
31740812
Source
pubmed
Published In
Nat Neurosci
Volume
23
Published Date
Start Page
5
End Page
14
DOI
10.1038/s41593-019-0538-5