Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway
Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway
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DOI：
10.1242/dev.067058
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发表时间：
2012-01
期刊：
影响因子：
4.6
通讯作者：
Masahide Sakabe;H. Kokubo;Y. Nakajima;Y. Saga
中科院分区：
文献类型：
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作者：
Masahide Sakabe;H. Kokubo;Y. Nakajima;Y. Saga
分子遗传学的发展使我们能够确定先天性心脏畸形的基因。然而，最近的研究表明，先天性心脏病不仅是由某些基因突变引起的，而且还可能是由异常的母体因素引起的。高浓度的母体视黄酸（RA），维生素A的活性衍生物，是众所周知的致畸剂，可以导致发育缺陷。我们以前的研究表明，在一个狭窄的发育窗口内向小鼠母体给予RA诱导流出道（OFT）间隔缺损，这是一种非常类似于人类大动脉转位（TGA）的疾病，尽管RA诱导TGA的责任因素和致病机制仍然未知。我们在此证明，Tbx 2在OFT心肌的表达是响应于RA，其下调与异常OFT的发展。我们发现，RA可以直接下调Tbx 2的表达，通过一个功能性视黄酸反应元件（RARE）的Tbx 2启动子区域，这也是所需的Tbx 2转录启动过程中OFT的发展。Tgfb 2的表达也下调RA处理的OFT区域，并上调Tbx 2在培养系统中。此外，在器官培养系统中加入TGFβ2可挽救过量RA引起的上皮-间质转化缺陷。这些数据表明，RA信号参与了Tbx 2的转录机制在OFT的发展和Tbx 2-TGFβ2级联是参与诱导TGA表型的关键途径之一。
The progress of molecular genetics has enabled us to identify the genes responsible for congenital heart malformations. However, recent studies suggest that congenital heart diseases are induced not only by mutations in certain genes, but also by abnormal maternal factors. A high concentration of maternal retinoic acid (RA), the active derivative of vitamin A, is well known as a teratogenic agent that can cause developmental defects. Our previous studies have shown that the maternal administration of RA to mice within a narrow developmental window induces outflow tract (OFT) septum defects, a condition that closely resembles human transposition of the great arteries (TGA), although the responsible factors and pathogenic mechanisms of the TGA induced by RA remain unknown. We herein demonstrate that the expression of Tbx2 in the OFT myocardium is responsive to RA, and its downregulation is associated with abnormal OFT development. We found that RA could directly downregulate the Tbx2 expression through a functional retinoic acid response element (RARE) in the Tbx2 promoter region, which is also required for the initiation of Tbx2 transcription during OFT development. Tgfb2 expression was also downregulated in the RA-treated OFT region and was upregulated by Tbx2 in a culture system. Moreover, defective epithelial-mesenchymal transition caused by the excess RA was rescued by the addition of Tgfβ2 in an organ culture system. These data suggest that RA signaling participates in the Tbx2 transcriptional mechanism during OFT development and that the Tbx2-Tgfβ2 cascade is one of the key pathways involved in inducing the TGA phenotype.