A5042684804- Genetics and Neurodevelopmental Disorders
- Neuroscience and Neuropharmacology Research
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Neurogenesis and neuroplasticity mechanisms
- Autism Spectrum Disorder Research
- RNA regulation and disease
- RNA and protein synthesis mechanisms
- CRISPR and Genetic Engineering
- Single-cell and spatial transcriptomics
- Receptor Mechanisms and Signaling
- Neural dynamics and brain function
- Nerve injury and regeneration
- Adipose Tissue and Metabolism
- RNA Interference and Gene Delivery
- Nuclear Receptors and Signaling
- RNA modifications and cancer
- Retinal Development and Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Cellular transport and secretion
- Animal Vocal Communication and Behavior
- Neurotransmitter Receptor Influence on Behavior
- Hearing, Cochlea, Tinnitus, Genetics
- Hormonal Regulation and Hypertension
Duke University
2016-2025
Duke Medical Center
2012-2024
Duke University Hospital
2012-2024
Applied Genetic Technologies (United States)
2021
Institute of Neurobiology
2014
Wellesley College
2011-2014
Liverpool Hospital
2013
London School of Hygiene & Tropical Medicine
2013
Åbo Akademi University
2008
University of Turku
2008
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, Rsks, catalyzed phosphorylation of pro-apoptotic BAD at serine 112 both in vitro and vivo. Rsk-induced suppressed BAD-mediated apoptosis neurons. Rsks also are known to phosphorylate transcription factor CREB (cAMP response element–binding protein) 133. Activated promoted survival, inhibition 133 triggered...
Mutations in MeCP2 , which encodes a protein that has been proposed to function as global transcriptional repressor, are the cause of Rett syndrome (RT T), an X-linked progressive neurological disorder. Although selective inactivation neurons is sufficient confer Rett-like phenotype mice, specific functions postmitotic not known. We find binds selectively BDNF promoter III and repress expression gene. Membrane depolarization triggers calcium-dependent phosphorylation release from III,...
Neuronal activity-inducible gene transcription correlates with rapid and transient increases in histone acetylation at promoters enhancers of activity-regulated genes. Exactly how modulates these genes has remained unknown. We used single-cell situ transcriptional analysis to show that Fos Npas4 are transcribed stochastic bursts mouse neurons membrane depolarization mRNA expression by increasing burst frequency. then expressed dCas9-p300 or dCas9-HDAC8 fusion proteins mimic block...
Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant use it the analysis genomes from nuclear with history familial thrombophilia. We demonstrate major allele results in improved genotype accuracy disease-associated variant loci. infer recombination sites to lowest median resolution demonstrated date (<1,000 base pairs). inheritance...
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 mice suggests that MECP2 gene replacement potential therapeutic option patients. We report improvements survival and phenotypic severity Mecp2-null male after neonatal intracranial delivery single-stranded (ss) AAV9/chicken β-actin (CBA)-MECP2 vector. Median was 16.6 weeks for MECP2-treated versus 9.3...
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 parallels those mediate human speech. We found ~10% of the avian genome were regulated by singing, and we a striking regional diversity both basal singing-induced programs four key song nuclei zebra finch, songbird. The region-enriched patterns result distinct combinations transcription factors (TFs), their...
To identify molecular mechanisms that control activity-dependent gene expression in the CNS, we have characterized factors mediate transcription of BDNF promoter III. We report identification a Ca(2+)-responsive E-box element, CaRE2, within III binds upstream stimulatory 1 and 2 (USF1/2) show USFs are required for activation CaRE2-dependent from find transcriptional activity is regulated by Ca(2+)-activated signaling pathways neurons bind to promoters number neuronal activity-regulated genes...
The Ca<sup>2+</sup>/calmodulin-activated kinases CaMKK2 and CaMKIV are highly expressed in the brain where they play important roles activating intracellular responses to elevated Ca<sup>2+</sup>. To address biological functions of Ca<sup>2+</sup> signaling via these during development, we have examined cerebellar development mice null for or CaMKIV. Here, demonstrate that CaMKK2/CaMKIV-dependent phosphorylation cAMP response element-binding protein (CREB) correlates with <i>Bdnf</i>...
The functional maturation of neurons is a prolonged process that extends past the mitotic exit and mediated by chromatin-dependent orchestration gene transcription programs. We find expression this program in mouse cerebellar granule (CGNs) requires dynamic changes genomic distribution histone H3 lysine 27 trimethylation (H3K27me3), demonstrating function for chromatin modification beyond its role cell fate specification. developmental loss H3K27me3 at promoters genes activated as CGNs...
Transcription of the gene encoding Brain-Derived Neurotropic Factor (BDNF) is induced in response to a wide variety extracellular stimuli via activation complex array transcription factors. However, what degree individual factors confer specificity upon regulation Bdnf poorly understood. Previous studies have shown that members myocyte enhancer factor 2 (MEF2) family bind regulatory element upstream promoter I and associate with an unknown binding site IV. Here we identify calcium-response 1...