2013年1月21日訊 /生物谷BIOON/ --NKX2.1 是呼吸系統(tǒng)祖細胞及甲狀腺上皮細胞的唯一的早期的標記,。NKX2.1 能調(diào)控許多肺特異性基因包括表面活性蛋白A,，B，C及CC-10和NKX2.1本身,。NKX2.1失活造成氣管食管瘺,，減少肺分支， 造成嚴重的肺發(fā)育不良,。如何調(diào)控NKX2.1表達一直是肺發(fā)育研究者需要解決的關(guān)鍵問題之一,。Yong Li等研究者在魯汶大學發(fā)現(xiàn)高水平的活化素-A能誘導人類胚胎干細胞 分化到內(nèi)胚層，持續(xù)高水平的活化素-A足以使內(nèi)胚層進一步誘導成FOXA2/NKX2-1/GATA6/PAX9陽性的呼吸內(nèi)胚層細胞,。這部分結(jié)果發(fā)表在《干細胞和發(fā)育》,。
活化素-A直接誘導NKX2-1表達機制是活化素-A給合ACVR2A， 招募ACVR1B(ALK4),，導致磷酸化SMAD2,，磷酸化SMAD2與SMAD4形成復(fù)合體，轉(zhuǎn)入細胞核內(nèi),，與NKX2-1基因啟動子直接結(jié)合并激活它的表達,。GDF11因能招募ALK4,，具有活化素-A相似的作用。但TGFb1,、Wnt3a,、SHH、FGF2及BMP4均不能誘導NKX2-1表達,。這個發(fā)現(xiàn)顛覆了當前有關(guān)NKX2.1調(diào)控的結(jié)果,，為研究肺發(fā)育提供了新的窗口。（生物谷Bioon.com）
doi:10.1089/scd.2012.0620
NKX2-1 activation by SMAD2 signaling after definitive endoderm differentiation in Human ESC
Yong Li, Kristel Eggermont, Veerle Vanslembrouck, Catherine Verfaillie
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 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 it’s expression. Activin-A can be replaced by GDF11 but not TGFb1. 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.
