Document Detail


SMAD7 directly converts human embryonic stem cells to telencephalic fate by a default mechanism.
MedLine Citation:
PMID:  23034881     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Human embryonic stem cells (hESCs) provide a valuable window into the dissection of the molecular circuitry underlying the early formation of the human forebrain. However, dissection of signaling events in forebrain development using current protocols is complicated by non-neural contamination and fluctuation of extrinsic influences. Here, we show that SMAD7, a cell-intrinsic inhibitor of transforming growth factor-β (TGFβ) signaling, is sufficient to directly convert pluripotent hESCs to an anterior neural fate. Time course gene expression revealed downregulation of MAPK components, and combining MEK1/2 inhibition with SMAD7-mediated TGFβ inhibition promoted telencephalic conversion. Fibroblast growth factor-MEK and TGFβ-SMAD signaling maintain hESCs by promoting pluripotency genes and repressing neural genes. Our findings suggest that in the absence of these cues, pluripotent cells simply revert to a program of neural conversion. Hence, the "primed" state of hESCs requires inhibition of the "default" state of neural fate acquisition. This has parallels in amphibians, suggesting an evolutionarily conserved mechanism.
Authors:
Mohammad Zeeshan Ozair; Scott Noggle; Aryeh Warmflash; Joanna Ela Krzyspiak; Ali H Brivanlou
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  31     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-21     Completed Date:  2013-06-24     Revised Date:  2014-07-21    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  35-47     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 AlphaMed Press.
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MeSH Terms
Descriptor/Qualifier:
Brain / embryology,  metabolism
Cell Line
Embryonic Stem Cells / cytology,  physiology*
Fibroblast Growth Factors / metabolism
Humans
MAP Kinase Signaling System
Mitogen-Activated Protein Kinases / metabolism
Neurogenesis
Pluripotent Stem Cells / metabolism
Smad7 Protein / metabolism*
Telencephalon / cytology*,  embryology*,  metabolism
Transforming Growth Factor beta / metabolism
Grant Support
ID/Acronym/Agency:
2R01HD032105/HD/NICHD NIH HHS; R01 GM101653/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/SMAD7 protein, human; 0/Smad7 Protein; 0/Transforming Growth Factor beta; 62031-54-3/Fibroblast Growth Factors; EC 2.7.11.24/Mitogen-Activated Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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