Document Detail

Retinoic acid synthesis promotes development of neural progenitors from mouse embryonic stem cells by suppressing endogenous, Wnt-dependent nodal signaling.
MedLine Citation:
PMID:  20665854     Owner:  NLM     Status:  MEDLINE    
Embryonic stem (ES) cells differentiate spontaneously toward a neuroectodermal fate in serum-free, adherent monocultures. Here, we show that this spontaneous neural fate requires retinoic acid (RA) synthesis. We monitor ES cells containing reporter genes for markers of the early neural plate as well as the primitive streak and its progeny to determine the cell fates induced when RA signaling is perturbed. We demonstrate that the spontaneous neural commitment of mouse ES cells requires endogenous RA production from vitamin A (vitA) in the medium. Formation of neural progenitors is inhibited by removing vitA from the medium, by inhibiting the enzymes that catalyze the synthesis of RA, or by inhibiting RA receptors. We show that subnanomolar concentrations of RA restore neuroectodermal differentiation when RA synthesis is blocked. We demonstrate that a neural to mesodermal fate change occurring when RA signaling is inhibited is dependent on Nodal-, Wnt-, and fibroblast growth factor-signaling. We show that Nodal suppresses neural development in a Wnt-dependent manner and that Wnt-mediated inhibition of neural development is reversed by inhibition of Nodal signaling. Together, our results show that neural induction in ES cells requires RA at subnanomolar levels to suppress Nodal signaling and suggest that the mechanism by which Wnt signaling suppresses neural development is through facilitation of Nodal signaling.
Nina Engberg; Morten Kahn; Dorthe Rønn Petersen; Mattias Hansson; Palle Serup
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  28     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-30     Completed Date:  2010-11-08     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1498-509     Citation Subset:  IM    
Department of Stem Cell Biology, Hagedorn Research Institute, Gentofte, Denmark.
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MeSH Terms
Cell Differentiation* / drug effects,  genetics
Cells, Cultured
Disulfiram / pharmacology
Embryonic Stem Cells / drug effects,  metabolism*
Enzyme Inhibitors / pharmacology
Fibroblast Growth Factors / metabolism
Gene Expression Regulation, Developmental
Genes, Reporter
Mesoderm / cytology,  metabolism
Monoterpenes / pharmacology
Neural Plate / cytology,  drug effects,  metabolism*
Neurons / drug effects,  metabolism*
Nodal Protein / metabolism*
Receptors, Retinoic Acid / antagonists & inhibitors,  metabolism
Signal Transduction* / drug effects
Time Factors
Tretinoin / metabolism*
Vitamin A / metabolism
Wnt Proteins / metabolism*
Reg. No./Substance:
0/AGN 193109; 0/Enzyme Inhibitors; 0/Monoterpenes; 0/Naphthalenes; 0/Nodal Protein; 0/Nodal protein, mouse; 0/Receptors, Retinoic Acid; 0/Wnt Proteins; 11103-57-4/Vitamin A; 302-79-4/Tretinoin; 5392-40-5/citral; 62031-54-3/Fibroblast Growth Factors; 97-77-8/Disulfiram

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

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