Dkk1-dependent inhibition of Wnt signaling activates Hesx1 expression through its 5' enhancer and directs forebrain precursor development.
Dkk1-dependent inhibition of Wnt signaling activates Hesx1 expression through its 5' enhancer and directs forebrain precursor development.
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Dkk1 依赖性 Wnt 信号传导抑制通过其 5 增强子激活 Hesx1 表达并指导前脑前体发育。
DOI：
10.1111/gtc.12136
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发表时间：
2014
期刊：
影响因子：
2.1
通讯作者：
Kondoh H.
中科院分区：
文献类型：
--
作者：
Matsuda K;Kondoh H.
前神经板（ANP）中前脑前体（AFBP）的发育取决于hesx1转录因子基因的激活。ANP的hesx1 -表达域由表达dkk1 -的组织构成，最初是近前内脏内胚层（AVE），后来是前中内胚层（AME）。AsDkk1‐缺失的胚胎不能发育hesx1‐表达域，很可能ANP中的Wnt信号抑制是hesx1激活所必需的。为了研究AFBP发育的调控，我们利用了外胚层干细胞（EpiSCs），它在缺乏激活素信号的情况下发育为ANP。hesx1和six3的表达均参与AFBP的发展，在去除激活素并同时添加Wnt信号抑制剂Dkk1或XAV939后2天被强烈激活。此外，我们发现720 - bpHesx15 '增强子的激活与AFBP中hesx1的表达有关，并依赖于Wnt信号抑制。此外，我们发现Wnt抑制在第一天比第二天对hesx1和six3的激活有更大的影响，这表明在胚胎中，由AVE衍生的Dkk1而不是AME衍生的Dkk1引起的Wnt抑制在AFBP的建立中发挥了重要作用。
Development of the anterior forebrain precursor (AFBP) in the anterior neural plate (ANP) depends on the activation of theHesx1transcription factor gene. TheHesx1‐expression domain of the ANP is underlain byDkk1‐expressing tissues, initially proximal‐most anterior visceral endoderm (AVE), and later anterior mesendoderm (AME). AsDkk1‐null embryos fail to develop theHesx1‐expressing domain, it is likely that Wnt signal inhibition in the ANP is required for theHesx1activation. To investigate the regulation of the AFBP development, we took advantage of epiblast stem cells (EpiSCs), which develop into the ANP in the absence of activin signaling. Expression ofHesx1andSix3, both involved in the AFBP development, was strongly activated 2 days after activin removal and concomitant addition of Wnt signal inhibitors, Dkk1 or XAV939. Furthermore, we showed that activation of the 720‐bpHesx15′ enhancer is responsible forHesx1expression in the AFBP and depends on Wnt signal inhibition. In addition, we showed that Wnt inhibition during the first day has larger impact on the activation ofHesx1andSix3than the second day, suggesting that in embryos Wnt inhibition caused by the AVE‐derived Dkk1, rather than the AME‐derived Dkk1, contributes greatly in the establishment of the AFBP.