Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs
Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs
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DOI：
10.1242/dev.02470
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发表时间：
2006-07
影响因子：
2.5
通讯作者：
Hidetaka Shiratori;K. Yashiro;M. Shen;H. Hamada
中科院分区：
文献类型：
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作者：
Hidetaka Shiratori;K. Yashiro;M. Shen;H. Hamada
Pitx 2在左侧发育中的内脏器官中表达，并与左右（LR）不对称器官发生有关。Pitx 2的不对称表达由一个包含多个Foxh 1结合位点和一个Nkx 2结合位点的内含子增强子（ASE）控制。这些结合位点对于不对称增强子活性是必需的和足够的，并且在脊椎动物中是进化上保守的。我们现在发现，缺乏Pitx 2 ASE的小鼠（Pitx 2 ΔASE/ΔASE小鼠）未能表现出左侧Pitx 2表达，并在大多数内脏器官中表现出偏侧性缺陷，尽管胃和心脏循环的位置不受影响。在某些领域，如共同的主静脉，不对称的Pitx 2的表达被认为是诱导的Nodal信号，但独立的ASE的Pitx 2。Pitx 2的表达似乎在野生型小鼠的大部分心室和房室管中被负反馈机制抑制，而此时该基因仍在其其他结构域中表达。在Pitx 2 ΔASE/ΔASE胚胎的左侧板中拯救早期的不对称Pitx 2表达不足以恢复正常的器官发生，这表明在左侧板谱系中Pitx 2的持续表达是部位特异性器官发生所必需的。
Pitx2 is expressed in developing visceral organs on the left side and is implicated in left-right (LR) asymmetric organogenesis. The asymmetric expression of Pitx2 is controlled by an intronic enhancer (ASE) that contains multiple Foxh1-binding sites and an Nkx2-binding site. These binding sites are essential and sufficient for asymmetric enhancer activity and are evolutionarily conserved among vertebrates. We now show that mice that lack the ASE of Pitx2 (Pitx2ΔASE/ΔASE mice) fail to manifest left-sided Pitx2 expression and exhibit laterality defects in most visceral organs, although the position of the stomach and heart looping remain unaffected. Asymmetric Pitx2 expression in some domains, such as the common cardinal vein, was found to be induced by Nodal signaling but to be independent of the ASE of Pitx2. Expression of Pitx2 appears to be repressed in a large portion of the heart ventricle and atrioventricular canal of wild-type mice by a negative feedback mechanism at a time when the gene is still expressed in its other domains. Rescue of the early phase of asymmetric Pitx2 expression in the left lateral plate of Pitx2ΔASE/ΔASE embryos was not sufficient to restore normal organogenesis, suggesting that continuous expression of Pitx2 in the lineage of the left lateral plate is required for situs-specific organogenesis.