Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway
Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway
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DOI：
10.1038/ng1446
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发表时间：
2004-11-01
期刊：
影响因子：
30.8
通讯作者：
Bhattacharya, S
中科院分区：
文献类型：
--
作者：
Bamforth, SD;Bragança, J;Bhattacharya, S
隔膜、流出道和主动脉弓的畸形是最常见的先天性心血管缺陷，并且发生在缺乏Cited 2（TFAP 2的转录共激活因子）的小鼠中。在这里，我们表明，Cited 2（-/-）小鼠也发展偏侧性缺陷，包括右异构，异常心脏循环和脾功能减退，这是抑制混合遗传背景。Cited 2（-/-）小鼠在左侧板中胚层中缺乏Nodal靶基因Pitx 2c、Nodal和Ebaf的表达，在左侧板中胚层中，它们是建立偏侧性和心血管发育所需的。在胚胎心脏中的Pitx 2c启动子处检测到CITED 2和TFAP 2，并且它们在瞬时转染测定中激活Pitx 2c转录。我们认为，异常的Nodal-Pitx 2c通路代表了在Cited 2（-/-）小鼠中观察到的心血管畸形的统一机制，并且这种畸形可能是偏侧性缺陷的唯一表现。
Malformations of the septum, outflow tract and aortic arch are the most common congenital cardiovascular defects and occur in mice lacking Cited2, a transcriptional coactivator of TFAP2. Here we show that Cited2(-/-) mice also develop laterality defects, including right isomerism, abnormal cardiac looping and hyposplenia, which are suppressed on a mixed genetic background. Cited2(-/-) mice lack expression of the Nodal target genes Pitx2c, Nodal and Ebaf in the left lateral plate mesoderm, where they are required for establishing laterality and cardiovascular development. CITED2 and TFAP2 were detected at the Pitx2c promoter in embryonic hearts, and they activate Pitx2c transcription in transient transfection assays. We propose that an abnormal Nodal-Pitx2c pathway represents a unifying mechanism for the cardiovascular malformations observed in Cited2(-/-) mice, and that such malformations may be the sole manifestation of a laterality defect.