期刊
CELL STEM CELL
卷 25, 期 1, 页码 103-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2019.04.021
关键词
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资金
- postdoctoral grant (Stanford) [ChEM-H112878]
- NIH [MH052804, MH092931]
- start-up funds from Colorado State University
- training grant from California Institute of Regenerative Medicine (CIRM) [TGR-01159]
- Singapore Agency for Science, Technology and Research (A*STAR)
- CIRM fellowship
- Larry L. Hillblom Foundation
- New York Stem Cell Foundation Robertson award
- Howard Hughes Medical Institute Faculty Scholar award
- Tashia and John Morgridge Faculty Scholar award by the Child Health Research Institute (CHRI) at Stanford
Human pluripotent stem cells can be rapidly converted into functional neurons by ectopic expression of proneural transcription factors. Here we show that directly reprogrammed neurons, despite their rapid maturation kinetics, can model teratogenic mechanisms that specifically affect early neurodevelopment. We delineated distinct phases of in vitro maturation during reprogramming of human neurons and assessed the cellular phenotypes of valproic acid (VPA), a teratogenic drug. VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons. These pathogenic effects were associated with VPA-mediated inhibition of the histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) pathways, which caused transcriptional downregulation of many genes, including MARCKSL1, an actin-stabilizing protein essential for dendritic morphogenesis and synapse maturation during early neurodevelopment. Our findings identify a developmentally restricted pathogenic mechanism of VPA and establish the use of reprogrammed neurons as an effective platform for modeling teratogenic pathways.
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