Aims The Cardiac Conduction System (CCS) is progressively specified during development by interactions among a discrete number of Transcriptions Factors that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain transcription factors (TFs) with multiple roles in mammalian development. In humans, Meis genes associate with congenital cardiac malformations and alterations of cardiac electrical activity, however the basis for these alterations has not been established. Here we studied the role of Meis transcription factors in cardiomyocyte development and function during mouse development and adult life. Methods and Results We studied Meis1 and Meis2 conditional deletion mouse models that allowed cardiomyocyte-specific elimination of Meis function during development and inducible elimination of Meis function in cardiomyocytes of the adult CCS. We studied cardiac anatomy, contractility and conduction. We report that Meis factors are global regulators of cardiac conduction, with a predominant role in the CCS. While constitutive Meis deletion in cardiomyocytes led to congenital malformations of the arterial pole and atria, as well as defects in ventricular conduction, Meis elimination in cardiomyocytes of the adult CCS produced sinus node dysfunction and delayed atrio-ventricular conduction. Molecular analyses unraveled Meis-controlled molecular pathways associated with these defects. Finally, we studied in transgenic mice the activity of a Meis1 human enhancer related to an SNP associated by GWAS to PR elongation and found that the transgene drives expression in components of the atrio-ventricular conduction system. Conclusions Our study identifies Meis TFs as essential regulators of the establishment of cardiac conduction function during development and its maintenance during adult life. In addition, we generated animal models and identified molecular alterations that will ease the study of Meis-associated conduction defects and congenital malformations in humans.

中文翻译：

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Meis 转录因子调节心脏传导系统的发育和成人功能


目的 心脏传导系统 （CCS） 在发育过程中通过离散数量的转录因子之间的相互作用逐渐指定，这些转录因子确保其正确的模式和其功能特性的出现。Meis 基因编码同源域转录因子 （TFs），在哺乳动物发育中具有多种作用。在人类中，Meis 基因与先天性心脏畸形和心脏电活动改变有关，但这些改变的基础尚未确定。在这里，我们研究了 Meis 转录因子在小鼠发育和成年期间心肌细胞发育和功能中的作用。方法和结果 我们研究了 Meis1 和 Meis2 条件缺失小鼠模型，这些模型允许在成年 CCS 的心肌细胞发育过程中特异性消除 Meis 功能，并诱导消除 Meis 功能。我们研究了心脏解剖结构、收缩力和传导。我们报道 Meis 因子是心脏传导的整体调节因子，在 CCS 中起主要作用。虽然心肌细胞中的组成型 Meis 缺失导致动脉极和心房的先天性畸形，以及心室传导缺陷，但成人 CCS 心肌细胞中的 Meis 消除产生了窦房结功能障碍和房室传导延迟。分子分析揭示了与这些缺陷相关的 Meis 控制的分子途径。最后，我们在转基因小鼠中研究了与 GWAS 与 PR 延伸相关的 SNP 相关的 Meis1 人类增强子的活性，发现转基因驱动房室传导系统成分的表达。 结论 我们的研究确定 Meis TFs 是发育过程中心脏传导功能建立和成年后维持心脏传导功能的重要调节因子。此外，我们生成了动物模型并确定了分子改变，这将简化对人类 Mis 相关传导缺陷和先天性畸形的研究。