Rationale:Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown.Objective:To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction.Methods and Results:ETS1 global and endothelial-specific knockout mice were used. Phenotypic assessments, RNA sequencing, and chromatin immunoprecipitation analysis were performed together with expression analysis, immunofluorescence and RNAscope in situ hybridization to uncover phenotypic and transcriptomic changes in response to loss of ETS1. Loss of ETS1 in endothelial cells causes ventricular noncompaction, reproducing the phenotype arising from global deletion of ETS1. Endothelial-specific deletion of ETS1 decreased the levels of Alk1 (activin receptor-like kinase 1), Cldn5 (claudin 5), Sox18 (SRY-box transcription factor 18), Robo4 (roundabout guidance receptor 4), Esm1 (endothelial cell specific molecule 1) and Kdr (kinase insert domain receptor), 6 important angiogenesis-relevant genes in endothelial cells, causing a coronary vasculature developmental defect in association with decreased compact zone cardiomyocyte proliferation. Downregulation of ALK1 expression in endocardium due to the loss of ETS1, along with the upregulation of TGF (transforming growth factor)-β1 and TGF-β3, occurred with increased TGFBR2/TGFBR1/SMAD2 signaling and increased extracellular matrix expression in the trabecular layer, in association with increased trabecular cardiomyocyte proliferation.Conclusions:These results demonstrate the importance of endothelial and endocardial ETS1 in cardiac development. Delineation of the gene regulatory network involving ETS1 in heart development will enhance our understanding of the molecular mechanisms underlying ventricular and coronary vascular developmental defects and will lead to improved approaches for the treatment of patients with congenital heart disease.

中文翻译：

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ETS1 内皮细胞缺失会损害冠状血管发育并导致心室致密化不全


理由：雅各布森综合征是一种罕见的染色体疾病，由人类 11 号染色体长臂缺失引起，导致包括先天性心脏缺陷在内的多种发育缺陷。人类和基因工程小鼠的联合研究表明，ETS1（E26 转化特异性 1）的缺失是雅各布森综合征先天性心脏缺陷的原因，但其潜在的分子和细胞机制尚不清楚。 目的：确定 ETS1 在心脏中的作用发育，特别是其在冠状动脉内皮和心内膜中的作用以及ETS1缺失导致冠状血管缺陷和心室致密化不全的机制。方法和结果：使用ETS1整体和内皮特异性敲除小鼠。表型评估、RNA 测序和染色质免疫沉淀分析与表达分析、免疫荧光和 RNAscope 原位杂交一起进行，以揭示 ETS1 丢失导致的表型和转录组变化。内皮细胞中 ETS1 的缺失会导致心室致密化不全，从而再现 ETS1 整体缺失所产生的表型。内皮特异性删除 ETS1 会降低 Alk1（激活素受体样激酶 1）、Cldn5（密蛋白 5）、Sox18（SRY 盒转录因子 18）、Robo4（迂回引导受体 4）、Esm1（内皮细胞特异性分子）的水平1) 和 Kdr（激酶插入结构域受体），内皮细胞中 6 个重要的血管生成相关基因，导致与致密区心肌细胞增殖减少相关的冠状血管发育缺陷。 由于 ETS1 缺失，心内膜中 ALK1 表达下调，同时 TGF（转化生长因子）-β1 和 TGF-β3 上调，伴随着 TGFBR2/TGFBR1/SMAD2 信号传导增加以及小梁层细胞外基质表达增加，与小梁心肌细胞增殖增加相关。结论：这些结果证明了内皮和心内膜 ETS1 在心脏发育中的重要性。描述心脏发育中涉及 ETS1 的基因调控网络将增强我们对心室和冠状血管发育缺陷的分子机制的理解，并将导致先天性心脏病患者治疗方法的改进。