Kodo Kazuki, Uchida Keiko, Yamagishi Hiroyuki
Division of Pediatric Cardiology, Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Front Cardiovasc Med. 2021 Mar 16;8:653244. doi: 10.3389/fcvm.2021.653244. eCollection 2021.
Congenital heart disease (CHD) is the most common life-threatening congenital anomaly. CHD occurs due to defects in cardiovascular development, and the majority of CHDs are caused by a multifactorial inheritance mechanism, which refers to the interaction between genetic and environmental factors. During embryogenesis, the cardiovascular system is derived from at least four distinct cell lineages: the first heart field, second heart field, cardiac neural crest, and proepicardial organ. Understanding the genes involved in each lineage is essential to uncover the genomic architecture of CHD. Therefore, we provide an overview of recent research progress using animal models and mutation analyses to better understand the molecular mechanisms and pathways linking cardiovascular development and CHD. For example, we highlight our recent work on genes encoding three isoforms of inositol 1,4,5-trisphosphate receptors (IPR1, 2, and 3) that regulate various vital and developmental processes, which have genetic redundancy during cardiovascular development. Specifically, IPR1 and 2 have redundant roles in the atrioventricular cushion derived from the first heart field lineage, whereas IPR1 and 3 exhibit redundancy in the right ventricle and the outflow tract derived from the second heart field lineage, respectively. Moreover, 22q11.2 deletion syndrome (22q11DS) is highly associated with CHD involving the outflow tract, characterized by defects of the cardiac neural crest lineage. However, our studies have shown that , a major genetic determinant of 22q11DS, was not expressed in the cardiac neural crest but rather in the second heart field, suggesting the importance of the cellular interaction between the cardiac neural crest and the second heart field. Comprehensive genetic analysis using the Japanese genome bank of CHD and mouse models revealed that a molecular regulatory network involving GATA6, FOXC1/2, TBX1, SEMA3C, and FGF8 was essential for reciprocal signaling between the cardiac neural crest and the second heart field during cardiovascular development. Elucidation of the genomic architecture of CHD using induced pluripotent stem cells and next-generation sequencing technology, in addition to genetically modified animal models and human mutation analyses, would facilitate the development of regenerative medicine and/or preventive medicine for CHD in the near future.
先天性心脏病（CHD）是最常见的危及生命的先天性异常。CHD是由于心血管发育缺陷所致，大多数CHD是由多因素遗传机制引起的，这是指遗传因素和环境因素之间的相互作用。在胚胎发生过程中，心血管系统至少源自四个不同的细胞谱系：第一心脏场、第二心脏场、心脏神经嵴和心外膜前体器官。了解每个谱系中涉及的基因对于揭示CHD的基因组结构至关重要。因此，我们概述了利用动物模型和突变分析的最新研究进展，以更好地理解连接心血管发育和CHD的分子机制和途径。例如，我们重点介绍了我们最近关于编码肌醇1,4,5-三磷酸受体三种异构体（IPR1、2和3）的基因的研究，这些受体调节各种重要和发育过程，在心血管发育过程中具有遗传冗余性。具体而言，IPR1和2在源自第一心脏场谱系的房室垫中具有冗余作用，而IPR1和3分别在源自第二心脏场谱系的右心室和流出道中表现出冗余性。此外，22q11.2缺失综合征（22q11DS）与涉及流出道的CHD高度相关，其特征是心脏神经嵴谱系的缺陷。然而，我们的研究表明，22q11DS的主要遗传决定因素不在心脏神经嵴中表达，而是在第二心脏场中表达，这表明心脏神经嵴和第二心脏场之间细胞相互作用的重要性。利用日本CHD基因组库和小鼠模型进行的综合遗传分析表明，涉及GATA6、FOXC1/2、TBX1、SEMA3C和FGF8的分子调控网络对于心血管发育过程中心脏神经嵴和第二心脏场之间的相互信号传导至关重要。除了基因改造动物模型和人类突变分析外，利用诱导多能干细胞和下一代测序技术阐明CHD的基因组结构，将有助于在不久的将来开发针对CHD的再生医学和/或预防医学。
