Runx1-Stat3-Tgfb3 signaling network regulating the anterior palatal development.
Runx1-Stat3-Tgfb3 signaling network regulating the anterior palatal development.
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DOI：
10.1038/s41598-018-29681-3
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发表时间：
2018-07-25
影响因子：
4.6
通讯作者：
Yamashiro T
中科院分区：
文献类型：
--
作者：
Sarper SE;Kurosaka H;Inubushi T;Ono Minagi H;Kuremoto KI;Sakai T;Taniuchi I;Yamashiro T
Runx 1缺陷导致小鼠在初级腭和次级腭之间的边界处以及次级腭的第一皱褶区域中的前部特异性腭裂。然而，这种区域特异性的细胞和分子发病机制仍然未知。在这项研究中，Runx 1上皮特异性缺失导致失败的接触腭上皮细胞的解体，并显着下调Tgfb 3表达在初级腭和鼻中隔。在培养中，TGFB 3蛋白拯救了突变体的分裂。此外，Stat 3磷酸化在Runx 1突变体中相应的裂缝区域受到干扰。Stat 3抑制剂处理后，Tgfb 3显著下调，培养中的腭融合缺陷表明Stat 3功能。因此，Tgfb 3是Runx 1信号传导的关键靶标，并且该信号传导轴可以由Stat 3激活介导。有趣的是，Socs 3的表达，Stat 3的抑制剂，是特定的在初级腭和上调Runx 1缺陷。因此，Socs 3参与Runx 1-Tgfb 3信号转导可能至少部分解释了Runx 1突变体中Tgfb 3表达和Stat 3活性的前特异性下调。这是第一个研究表明，新的Runx 1-Stat 3-Tgfb 3轴是必不可少的前腭发生。
Runx1 deficiency results in an anteriorly specific cleft palate at the boundary between the primary and secondary palates and in the first rugae area of the secondary palate in mice. However, the cellular and molecular pathogenesis underlying such regional specificity remain unknown. In this study, Runx1 epithelial-specific deletion led to the failed disintegration of the contacting palatal epithelium and markedly downregulated Tgfb3 expression in the primary palate and nasal septum. In culture, TGFB3 protein rescued the clefting of the mutant. Furthermore, Stat3 phosphorylation was disturbed in the corresponding cleft regions in Runx1 mutants. The Stat3 function was manifested by palatal fusion defects in culture following Stat3 inhibitor treatment with significant downregulation of Tgfb3. Tgfb3 is therefore a critical target of Runx1 signaling, and this signaling axis could be mediated by Stat3 activation. Interestingly, the expression of Socs3, an inhibitor of Stat3, was specific in the primary palate and upregulated by Runx1 deficiency. Thus, the involvement of Socs3 in Runx1-Tgfb3 signaling might explain, at least in part, the anteriorly specific downregulation of Tgfb3 expression and Stat3 activity in Runx1 mutants. This is the first study to show that the novel Runx1-Stat3-Tgfb3 axis is essential in anterior palatogenesis.
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影响因子：
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