Cooperative and antagonistic roles for Irx3 and Irx5 in cardiac morphogenesis and postnatal physiology
Cooperative and antagonistic roles for Irx3 and Irx5 in cardiac morphogenesis and postnatal physiology
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DOI：
10.1242/dev.081703
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发表时间：
2012-11-01
期刊：
影响因子：
4.6
通讯作者：
Bruneau, Benoit G.
中科院分区：
文献类型：
--
作者：
Gaborit, Nathalie;Sakuma, Rui;Bruneau, Benoit G.
易洛魁人同源异型框（Irx）同源异型域转录因子对胚胎发育的几个方面都很重要。在发育中的心脏中，单个Irx基因对某些出生后心脏功能很重要，包括心脏复极（Irx5）和快速心室传导（Irx3）。Irx基因在发育中的心脏中以动态和部分重叠的模式表达。在这里，我们表明，在小鼠Irx3和Irx5有多余的功能，在内皮细胞调节房室管形态发生和流出道的形成。我们的数据表明，直接转录抑制Bmp10的Irx3和Irx5在endoepithelium是需要心室分隔。出生后心肌中Irx3和Irx5的缺失导致房室传导延长，部分原因是Na+通道蛋白Nav1.5的表达激活。令人惊讶的是，出生后Irx3和Irx5的组合损失导致在Irx5突变心脏中改变的复极梯度的恢复，这表明出生后Irx3活性可以被Irx5抑制。我们的研究结果揭示了Irx3和Irx5在胚胎心脏发育和出生后生理学中的复杂遗传相互作用。
The Iroquois homeobox (Irx) homeodomain transcription factors are important for several aspects of embryonic development. In the developing heart, individual Irx genes are important for certain postnatal cardiac functions, including cardiac repolarization (Irx5) and rapid ventricular conduction (Irx3). Irx genes are expressed in dynamic and partially overlapping patterns in the developing heart. Here we show in mice that Irx3 and Irx5 have redundant function in the endocardium to regulate atrioventricular canal morphogenesis and outflow tract formation. Our data suggest that direct transcriptional repression of Bmp10 by Irx3 and Irx5 in the endocardium is required for ventricular septation. A postnatal deletion of Irx3 and Irx5 in the myocardium leads to prolongation of atrioventricular conduction, due in part to activation of expression of the Na+ channel protein Nav1.5. Surprisingly, combined postnatal loss of Irx3 and Irx5 results in a restoration of the repolarization gradient that is altered in Irx5 mutant hearts, suggesting that postnatal Irx3 activity can be repressed by Irx5. Our results have uncovered complex genetic interactions between Irx3 and Irx5 in embryonic cardiac development and postnatal physiology.