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Elife. 2013 Sep 10;2:e00508. doi: 10.7554/eLife.00508.

Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells.

Author information

1
Department of Bioengineering and Therapeutic Science , University of California, San Francisco , San Francisco , United States ; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research , University of California, San Francisco , San Francisco , United States ; Programs in Human Genetics and Biological Sciences , University of California, San Francisco , San Francisco , United States.

Abstract

Mammalian pluripotent stem cells (PSCs) represent an important venue for understanding basic principles regulating tissue-specific differentiation and discovering new tools that may facilitate clinical applications. Mechanisms that direct neural differentiation of PSCs involve growth factor signaling and transcription regulation. However, it is unknown whether and how electrical activity influences this process. Here we report a high throughput imaging-based screen, which uncovers that selamectin, an anti-helminthic therapeutic compound with reported activity on invertebrate glutamate-gated chloride channels, promotes neural differentiation of PSCs. We show that selamectin's pro-neurogenic activity is mediated by γ2-containing GABAA receptors in subsets of neural rosette progenitors, accompanied by increased proneural and lineage-specific transcription factor expression and cell cycle exit. In vivo, selamectin promotes neurogenesis in developing zebrafish. Our results establish a chemical screening platform that reveals activity-dependent neural differentiation from PSCs. Compounds identified in this and future screening might prove therapeutically beneficial for treating neurodevelopmental or neurodegenerative disorders. DOI:http://dx.doi.org/10.7554/eLife.00508.001.

KEYWORDS:

E. coli; Mouse; Zebrafish; cellular differentiation; chemical genetics; dopaminergic neurons; pluripotent stem cells; small molecule tool

PMID:
24040509
PMCID:
PMC3771564
DOI:
10.7554/eLife.00508
[Indexed for MEDLINE]
Free PMC Article
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