Tie1 is a receptor tyrosine kinase expressed in endothelial cells, where it modulates Angiopoietin/Tie2 signaling. Previous studies have shown that mouse Tie1 mutants exhibit severe cardiovascular defects; however, much remains to be learned about the role of Tie1, especially during cardiac development. To further understand Tie1 function, we generated a zebrafish tie1 mutant line. Homozygous mutant embryos display reduced endothelial and endocardial cell numbers and reduced heart size. Live imaging and ultrastructural analyses at embryonic stages revealed increased cardiac jelly thickness as well as cardiomyocyte defects, including a loss of sarcomere organization and altered cell shape. Transcriptomic profiling of embryonic hearts uncovered the downregulation of tll1, which encodes a Tolloid-like protease, in tie1^−/− compared with wild-type siblings. Using mRNA injections into one-cell stage embryos, we found that tll1 overexpression could partially rescue the tie1 mutant cardiac phenotypes including the endocardial and myocardial cell numbers as well as the cardiac jelly thickness. Altogether, our results indicate the importance of a Tie1-Tolloid-like 1 axis in paracrine signaling during cardiac development.

Tie1是在内皮细胞中表达的受体酪氨酸激酶，在其中调节血管生成素/ Tie2信号传导。先前的研究表明，小鼠Tie1突变体表现出严重的心血管缺陷；因此，这种突变是可能的。然而，关于Tie1的作用，尤其是在心脏发育过程中，还有很多事情要学习。为了进一步了解Tie1功能，我们生成了一条斑马鱼tie1突变株。纯合突变体胚胎显示内皮细胞和心内膜细胞数量减少，心脏大小减少。胚胎期的实时成像和超微结构分析显示，心cardiac厚度增加以及心肌细胞缺陷，包括肌节组织的丧失和细胞形状的改变。胚胎心脏的转录组分析揭示了tll1的下调。与野生型同胞相比，tie1 ^-/-中编码Tolloid-样蛋白酶的，。使用单细胞期胚胎中的mRNA注射，我们发现tll1的过表达可以部分挽救tie1突变型心脏表型，包括心内膜和心肌细胞数以及心胶厚度。总之，我们的结果表明在心脏发育过程中，Tie1-Tolloid样1轴在旁分泌信号传导中的重要性。