1. NKX2-1 Activation by SMAD2 Signaling After Definitive Endoderm Differentiation in Human Embryonic Stem Cell
- Author
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Kristel Eggermont, Catherine M. Verfaillie, Yong Li, and Veerle Vanslembrouck
- Subjects
animal structures ,Cellular differentiation ,Respiratory System ,Thyroid Nuclear Factor 1 ,Smad2 Protein ,Biology ,Cell Line ,stomatognathic system ,Original Research Reports ,medicine ,Humans ,Phosphorylation ,Promoter Regions, Genetic ,Transcription factor ,Embryonic Stem Cells ,Regulation of gene expression ,Binding Sites ,Endoderm ,Growth differentiation factor ,Nuclear Proteins ,Correction ,Cell Differentiation ,Cell Biology ,Hematology ,respiratory system ,Molecular biology ,Embryonic stem cell ,Cell biology ,Activins ,Growth Differentiation Factors ,medicine.anatomical_structure ,Gene Expression Regulation ,Bone Morphogenetic Proteins ,embryonic structures ,cardiovascular system ,Signal transduction ,Protein Processing, Post-Translational ,Developmental Biology ,Definitive endoderm ,Protein Binding ,Signal Transduction ,Transcription Factors - 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 β1. 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.
- Published
- 2012