Evolutionary conservation of Nkx2.5 autoregulation in the second heart field.
Evolutionary conservation of Nkx2.5 autoregulation in the second heart field.
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DOI：
10.1016/j.ydbio.2012.11.007
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发表时间：
2013-02-01
影响因子：
2.7
通讯作者：
Lee, Kyu-Ho
中科院分区：
文献类型：
--
作者：
Clark, Christopher D.;Zhang, Boding;Lee, Benjamin;Evans, Samuel I.;Lassar, Andrew B.;Lee, Kyu-Ho
关键词：
心脏同源异型盒基因Nkx2.5在流出道和右心室与第二心野（SHF）祖细胞的分化过程中起着关键和剂量敏感的作用，Nkx2.5突变与人类流出道先天性心脏病（OFT CHD）密切相关。因此，确定控制SHF人群中Nkx2.5表达的调节机制对于理解复杂CHD的病因具有重要作用。通过对鸡和小鼠中控制Nkx2.5 SHF表达的调节元件的比较分析，我们发现证据表明Nkx2.5自动调节对于维持这两个物种SHF分化期间Nkx2.5的表达非常重要。然而，Nkx2.5的维持机制在胎盘哺乳动物和非哺乳类脊椎动物之间是不同的：在鸡中，Nkx2.5直接与维持SHF中Nkx2.5表达所需的基因组增强子元件结合。此外，鉴于其他非哺乳类脊椎动物拥有类似的基因组结构，这可能也是真的。相比之下，在胎盘哺乳动物中，SHF中的Nkx2.5自动调节通过Mef2c间接发挥作用。这些数据强调了哺乳动物中Nkx2.5和Mef2c在SHF转录调控中的紧密关系，并强调了进化顺式调控分析的潜力，以确定控制心脏发育的基因网络的核心保守组分。
The cardiac homeobox gene Nkx2.5 plays a key and dosage-sensitive role in the differentiation of outflow tract and right ventricle from progenitors of the second heart field (SHF) and Nkx2.5 mutation is strongly associated with human outflow tract congenital heart disease (OFT CHD). Therefore defining the regulatory mechanisms controlling Nkx2.5 expression in SHF populations serves an important function in understanding the etiology of complex CHD. Through a comparative analysis of regulatory elements controlling SHF expression of Nkx2.5 in the chicken and mouse, we have found evidence that Nkx2.5 autoregulation is important for maintaining Nkx2.5 expression during SHF differentiation in both species. However the mechanism of Nkx2.5 maintenance differs between placental mammals and non-mammalian vertebrates: In chick Nkx2.5 binds directly to a genomic enhancer element that is required to maintain Nkx2.5 expression in the SHF. In addition, it is likely that this is true in other non-mammalian vertebrates given that they possess a similar genomic organization. By contrast, in placental mammals, Nkx2.5 autoregulation in the SHF functions indirectly through Mef2c. These data underscore a tight relationship in mammals between Nkx2.5 and Mef2c in SHF transcriptional regulation, and highlight the potential for evolutionary cis-regulatory analysis to identify core, conserved components of the gene networks controlling heart development.
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