2013年1月21日讯 /生物谷BIOON/ --NKX2.1 是呼吸系统祖细胞及甲状腺上皮细胞的唯一的早期的标记。NKX2.1 能调控许多肺特异性基因包括表面活性蛋白A，B，C及CC-10和NKX2.1本身。NKX2.1失活造成气管食管瘘，减少肺分支， 造成严重的肺发育不良。如何调控NKX2.1表达一直是肺发育研究者需要解决的关键问题之一。Yong Li等研究者在鲁汶大学发现高水平的活化素-A能诱导人类胚胎干细胞 分化到内胚层，持续高水平的活化素-A足以使内胚层进一步诱导成FOXA2/NKX2-1/GATA6/PAX9阳性的呼吸内胚层细胞。这部分结果发表在《干细胞和发育》。
活化素-A直接诱导NKX2-1表达机制是活化素-A给合ACVR2A， 招募ACVR1B(ALK4)，导致磷酸化SMAD2，磷酸化SMAD2与SMAD4形成复合体，转入细胞核内，与NKX2-1基因启动子直接结合并激活它的表达。GDF11因能招募ALK4，具有活化素-A相似的作用。但TGFb1、Wnt3a、SHH、FGF2及BMP4均不能诱导NKX2-1表达。这个发现颠覆了当前有关NKX2.1调控的结果，为研究肺发育提供了新的窗口。（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.
