Tbx1 is regulated by forkhead proteins in the secondary heart field
Tbx1 is regulated by forkhead proteins in the secondary heart field
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DOI：
10.1002/dvdy.20686
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发表时间：
2006-03-01
影响因子：
2.5
通讯作者：
Srivastava, D
中科院分区：
文献类型：
--
作者：
Maeda, J;Yamagishi, H;Srivastava, D
以组织特异性和定量的方式进行转录调控对于发育事件至关重要，包括那些涉及心血管形态发生的事件。Tbx1是一种含T - box的转录因子，它是人类22q11缺失综合征中所观察到的许多缺陷的原因。Tbx1在第二心脏区（SHF）表达，对心脏流出道（OFT）的发育至关重要。我们之前报道过，在头部间充质和咽内胚层中，Tbx1受音猬因子通过叉头（Fox）转录因子调控，但它在SHF中是如何被调控的尚不清楚。在此，我们表明SHF中的Tbx1表达受Fox蛋白通过两个进化上保守的Fox结合位点以剂量依赖的方式调控。利用Tbx1增强子进行的细胞命运分析表明，在早期发育过程中，源自SHF的表达Tbx1的细胞对右心室心肌以及流出道有广泛贡献，并最终形成右心室漏斗部、肺动脉干和肺动脉瓣。这些结果表明，Fox蛋白参与了大多数（如果不是全部的话）Tbx1表达区域，并且Tbx1标记了一部分源自SHF的细胞，特别是那些对右侧流出道和近端肺动脉有独特贡献的细胞。
Transcriptional regulation in a tissue-specific and quantitative manner is essential for developmental events, including those involved in cardiovascular morphogenesis. Tbx1 is a T-box-containing transcription factor that is responsible for many of the defects observed in 22q11 deletion syndrome in humans. Tbx1 is expressed in the secondary heart field (SHF) and is essential for cardiac outflow tract (OFT) development. We previously reported that Tbx1 is regulated by sonic hedgehog by means of forkhead (Fox) transcription factors in the head mesenchyme and pharyngeal endoderm, but how it is regulated in the SHF is unknown. Here, we show that Tbx1 expression in the SHIP is regulated by Fox proteins through a combination of two evolutionarily conserved Fox binding sites in a dose-dependent manner. Cell fate analysis using the Tbx1 enhancer suggests that SHF-derived Tbx1-expressing cells contribute extensively to the right ventricular myocardium as well as the OFT during early development and ultimately give rise to the right ventricular infundibulum, pulmonary trunk, and pulmonary valves. These results suggest that Fox proteins are involved in most, if not all, Tbx1 expression domains and that Tbx1 marks a subset of SHF-derived cells, particularly those that uniquely contribute to the right-sided outflow tract and proximal pulmonary artery.