DeMoya Ricardo A, Forman-Rubinsky Rachel E, Fontaine Deon, Shin Joseph, Watkins Simon C, Lo Cecilia, Tsang Michael
Department of Developmental Biology, University of Pittsburgh, School of Medicine, Pittsburgh PA 15213, USA.
Department of Cell Biology and Molecular Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
bioRxiv. 2023 Mar 31:2023.03.30.534737. doi: 10.1101/2023.03.30.534737.
Hypoplastic left heart syndrome (HLHS) is a congenital heart disease where the left ventricle is reduced in size. A forward genetic screen in mice identified SIN3A associated protein 130kDa ( ), a protein in the chromatin modifying SIN3A/HDAC1 complex, as a gene contributing to the digenic etiology of HLHS. Here, we report the role of zebrafish genes in heart development. Loss of one of two orthologs, resulted in smaller ventricle size, a phenotype reminiscent to the hypoplastic left ventricle in mice. While cardiac progenitors were normal during somitogenesis, diminution of the ventricle size suggest the Second Heart Field (SHF) was the source of the defect. To explore the role of in gene regulation, transcriptome profiling was performed after the heart tube formation to identify candidate pathways and genes responsible for the small ventricle phenotype. Genes involved in cardiac differentiation and cell communication were dysregulated in , but not in mutants. Confocal light sheet analysis measured deficits in cardiac output in supporting the notion that cardiomyocyte maturation was disrupted. Lineage tracing experiments revealed a significant reduction of SHF cells in the ventricle that resulted in increased outflow tract size. These data suggest that is involved in cardiogenesis via regulating the accretion of SHF cells to the growing ventricle and in their subsequent maturation for cardiac function. Further, genetic studies revealed an interaction between and , in the incidence of small ventricles. These studies highlight the conserved role of Sap130a and Hdac1 in zebrafish cardiogenesis.
左心发育不全综合征（HLHS）是一种先天性心脏病，其左心室尺寸减小。在小鼠中进行的正向遗传学筛选确定了SIN3A相关蛋白130kDa（ ），一种染色质修饰SIN3A/HDAC1复合物中的蛋白质，是导致HLHS双基因病因的一个基因。在此，我们报告斑马鱼 基因在心脏发育中的作用。两个直系同源基因之一的缺失导致心室尺寸变小，这一表型让人联想到小鼠中的左心室发育不全。虽然在体节形成期间心脏祖细胞正常，但心室尺寸减小表明第二心脏场（SHF）是缺陷的来源。为了探究 在基因调控中的作用，在心脏管形成后进行转录组分析，以确定导致小心室表型的候选途径和基因。参与心脏分化和细胞通讯的基因在 中失调，但在 突变体中未失调。共聚焦光片分析测量了 中心输出量的缺陷，支持心肌细胞成熟受到破坏的观点。谱系追踪实验显示心室中SHF细胞显著减少，导致流出道尺寸增加。这些数据表明 通过调节SHF细胞向生长中的心室的积聚及其随后为心脏功能的成熟而参与心脏发生。此外，遗传学研究揭示了 和 在小心室发生率方面的相互作用。这些研究突出了Sap130a和Hdac1在斑马鱼心脏发生中的保守作用。
