Stem Cells Dev. 2013 May 1;22(9):1433-42.

NKX2-1 activation by SMAD2 signaling after definitive endoderm differentiation in human embryonic stem cell.

Li Y, Eggermont K, Vanslembrouck V, Verfaillie CM.

Interdepartmentaal Stamcelinstituut, Katholieke Universiteit Leuven, Leuven, Belgium.

 

Abstract

Expression of NKX2-1 is required to specify definitive endoderm to respiratory endoderm. However, the transcriptional regulation of NKX2-1 is not fully understood. Here we demonstrate that aside from specifying undifferentiated human embryonic stem cell (hESC) to definitive endoderm, high concentrations of Activin-A are also necessary and sufficient to induce hESC-derived definitive endodermal progeny to a FOXA2/NKX2-1/GATA6/PAX9 positive respiratory epithelial fate. Activin-A directly mediates the induction of NKX2-1 by interacting with ALK4, leading to phosphorylation of SMAD2, which binds directly to the NKX2-1 promoter and activates its expression. Activin-A can be replaced by GDF11 but not transforming growth factor ╬▓1. Addition of Wnt3a, SHH, FGF2, or BMP4 failed to induce NKX2-1. These results suggest that direct binding of Activin-A-responsive SMAD2 to the NKX2-1 promoter plays essential role during respiratory endoderm specification.

PMID: 23259454

 

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Fig 1. Model of SMAD Regulation of NKX2-1 transcription in Human pluripotent  stem cells (hPS). hPS can be committed to mesendoderm (ME)/DE with high concentration Activin A through TGF-beta pathway. NKX2.1 was reduced after continuous exposure Activin A.

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