Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
Development. 2012 Nov;139(21):4007-19. doi: 10.1242/dev.081703. Epub 2012 Sep 19.
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.
伊洛魁同源盒（Irx）同源结构域转录因子对于胚胎发育的几个方面都很重要。在发育中的心脏中，单个 Irx 基因对于某些出生后的心脏功能很重要，包括心脏复极化（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，我们在小鼠中表明，Irx3 和 Irx5 在心内膜中有冗余功能，可调节房室管形态发生和流出道形成。我们的数据表明，Irx3 和 Irx5 在心内膜中对 Bmp10 的直接转录抑制是室间隔形成所必需的。心肌中 Irx3 和 Irx5 的出生后缺失会导致房室传导延长，部分原因是激活了 Na(+)通道蛋白 Nav1.5 的表达。令人惊讶的是，Irx3 和 Irx5 的联合出生后缺失导致复极化梯度恢复，这在 Irx5 突变心脏中发生了改变，表明出生后 Irx3 的活性可以被 Irx5 抑制。我们的结果揭示了 Irx3 和 Irx5 在胚胎心脏发育和出生后生理之间的复杂遗传相互作用。
