Celltec-UB, Department of Cell Biology, Physiology, and Immunology, Faculty of Biology, University of Barcelona, Barcelona 08028, Spain.
Institute of Biomedicine (IBUB), University of Barcelona, Barcelona 08028, Spain.
Development. 2023 Mar 15;150(6). doi: 10.1242/dev.201147. Epub 2023 Mar 27.
Wt1 encodes a zinc finger protein that is crucial for epicardium development. Although WT1 is also expressed in coronary endothelial cells (ECs), the abnormal heart development observed in Wt1 knockout mice is mainly attributed to its functions in the epicardium. Here, we have generated an inducible endothelial-specific Wt1 knockout mouse model (Wt1KOΔEC). Deletion of Wt1 in ECs during coronary plexus formation impaired coronary blood vessels and myocardium development. RNA-Seq analysis of coronary ECs from Wt1KOΔEC mice demonstrated that deletion of Wt1 exerted a major impact on the molecular signature of coronary ECs and modified the expression of several genes that are dynamically modulated over the course of coronary EC development. Many of these differentially expressed genes are involved in cell proliferation, migration and differentiation of coronary ECs; consequently, the aforementioned processes were affected in Wt1KOΔEC mice. The requirement of WT1 in coronary ECs goes beyond the initial formation of the coronary plexus, as its later deletion results in defects in coronary artery formation. Through the characterization of these Wt1KOΔEC mouse models, we show that the deletion of Wt1 in ECs disrupts physiological blood vessel formation.
WT1 编码一种锌指蛋白，对于心外膜的发育至关重要。尽管 WT1 也在心冠状内皮细胞（EC）中表达，但在 WT1 敲除小鼠中观察到的异常心脏发育主要归因于其在心外膜中的功能。在这里，我们生成了一种可诱导的内皮细胞特异性 WT1 敲除小鼠模型（Wt1KOΔEC）。在冠状动脉丛形成过程中内皮细胞中 WT1 的缺失损害了冠状动脉血管和心肌的发育。来自 Wt1KOΔEC 小鼠的冠状动脉 EC 的 RNA-Seq 分析表明，WT1 的缺失对冠状动脉 EC 的分子特征产生了重大影响，并改变了几个在冠状动脉 EC 发育过程中动态调节的基因的表达。这些差异表达的基因中的许多涉及冠状动脉 EC 的细胞增殖、迁移和分化；因此，上述过程在 Wt1KOΔEC 小鼠中受到影响。WT1 在冠状动脉 EC 中的作用超出了冠状动脉丛的初始形成，因为其后期缺失会导致冠状动脉形成缺陷。通过对这些 Wt1KOΔEC 小鼠模型的表征，我们表明 EC 中 WT1 的缺失破坏了生理性血管形成。
