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    Ethanol Diverts Early Neuronal Differentiation Trajectory of Embryonic Stem Cells by Disrupting the Balance of Lineage Specifiers

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    Ethanol diverts early neuronal ...
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    Genre
    Journal Article
    Date
    2013-05-28
    Author
    Sánchez-Alvarez, R
    Gayen, S
    Vadigepalli, R
    Anni, H
    Subject
    Actin Cytoskeleton
    Animals
    Apoptosis
    Cell Differentiation
    Cell Lineage
    Cell Proliferation
    Cell Shape
    Cytoskeleton
    Embryonic Stem Cells
    Ethanol
    Gene Expression Profiling
    Gene Expression Regulation
    Mice
    Microfluidics
    Models, Biological
    Neurons
    Signal Transduction
    Transcription Factors
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    Permanent link to this record
    http://hdl.handle.net/20.500.12613/5397
    
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    DOI
    10.1371/journal.pone.0063794
    Abstract
    Background:Ethanol is a toxin responsible for the neurodevelopmental deficits of Fetal Alcohol Spectrum Disorders (FASD). Recent evidence suggests that ethanol modulates the protein expression of lineage specifier transcription factors Oct4 (Pou5f1) and Sox2 in early stages of mouse embryonic stem (ES) cell differentiation. We hypothesized that ethanol induced an imbalance in the expression of Oct4 and Sox2 in early differentiation, that dysregulated the expression of associated and target genes and signaling molecules and diverted cells from neuroectodermal (NE) formation.Methodology/Principal Findings:We showed modulation by ethanol of 33 genes during ES cell differentiation, using high throughput microfluidic dynamic array chips measuring 2,304 real time quantitative PCR assays. Based on the overall gene expression dynamics, ethanol drove cells along a differentiation trajectory away from NE fate. These ethanol-induced gene expression changes were observed as early as within 2 days of differentiation, and were independent of cell proliferation or apoptosis. Gene expression changes were correlated with fewer βIII-tubulin positive cells of an immature neural progenitor phenotype, as well as a disrupted actin cytoskeleton were observed. Moreover, Tuba1a and Gapdh housekeeping genes were modulated by ethanol during differentiation and were replaced by a set of ribosomal genes with stable expression.Conclusions/Significance:These findings provided an ethanol-response gene signature and pointed to the transcriptional dynamics underlying lineage imbalance that may be relevant to FASD phenotype. © 2013 Sánchez-Alvarez et al.
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    PLoS ONE
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    http://dx.doi.org/10.34944/dspace/5379
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