PDF(Pubmed)
Abstract：
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 130 kDa (Sap130), part of the chromatin modifying SIN3A/HDAC complex, as a gene contributing to the etiology of HLHS. Here, we report the role of zebrafish sap130 genes in heart development. Loss of sap130a, one of two Sap130 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 sap130a 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 cardiac function were dysregulated in sap130a, but not in sap130b mutants. Confocal light sheet analysis measured deficits in cardiac output in MZsap130a 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 sap130a 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 hdac1 and sap130a, in the incidence of small ventricles. These studies highlight the conserved role of Sap130a and Hdac1 in zebrafish cardiogenesis.
摘要：
左心发育不全综合征(HLHS)是一种先天性心脏病,其中左心室尺寸减小。小鼠的正向遗传筛选鉴定了SIN3A相关蛋白130kDa（Sap130），染色质修饰SIN3A/HDAC复合物的一部分，作为导致HLHS病因的基因。这里,我们报道了斑马鱼sap130基因在心脏发育中的作用。SAP130A的损失，两个Sap130直系同源物之一，导致更小的心室大小，一种让人联想到小鼠左心室发育不全的表型。虽然心脏祖细胞在体发生期间是正常的，心室大小的减小提示第二心脏区域（SHF）是缺损的来源。探讨sap130a在基因调控中的作用,在心脏管形成后进行转录组分析以鉴定负责小心室表型的候选途径和基因。参与心脏分化和心脏功能的基因在sap130a中失调，但不是在sap130b突变体中。共聚焦光片分析测量了MZsap130a中的心输出量不足，支持心肌细胞成熟被破坏的观点。谱系追踪实验显示，心室中SHF细胞的显着减少导致流出道大小增加。这些数据表明，sap130a通过调节SHF细胞向生长的心室的增生以及随后的心脏功能成熟而参与心脏发生。Further,遗传研究揭示了hdac1和sap130a之间的相互作用，在小脑室的发病率。这些研究强调了Sap130a和Hdac1在斑马鱼心脏发生中的保守作用。
