Abstract：
Development of the vascular system is regulated by multiple signaling pathways mediated by receptor tyrosine kinases. Among them, angiopoietin (Ang)/Tie signaling regulates lymphatic and blood vessel development in mammals. Of the two Tie receptors, Tie2 is well known as a key mediator of Ang/Tie signaling, but, unexpectedly, recent studies have revealed that the Tie2 locus has been lost in many vertebrate species, whereas the Tie1 gene is more commonly present. However, Tie1-driven signaling pathways, including ligands and cellular functions, are not well understood. Here, we performed comprehensive mutant analyses of angiopoietins and Tie receptors in zebrafish and found that only angpt1 and tie1 mutants show defects in trunk lymphatic vessel development. Among zebrafish angiopoietins, only Angpt1 binds to Tie1 as a ligand. We indirectly monitored Ang1/Tie1 signaling and detected Tie1 activation in sprouting endothelial cells, where Tie1 inhibits nuclear import of EGFP-Foxo1a. Angpt1/Tie1 signaling functions in endothelial cell migration and proliferation, and in lymphatic specification during early lymphangiogenesis, at least in part by modulating Vegfc/Vegfr3 signaling. Thus, we show that Angpt1/Tie1 signaling constitutes an essential signaling pathway for lymphatic development in zebrafish.
摘要：
血管系统的发育受受体酪氨酸激酶（RTK）介导的多种信号通路调节。其中,血管生成素（Ang）/Tie信号调节哺乳动物的淋巴和血管发育。在两个受体中，众所周知，Tie2是Ang/Tie信令的关键介体，但出乎意料的是，最近的研究表明，Tie2位点已经在许多脊椎动物物种中丢失，而Tie1基因更常见。然而,Tie1驱动的信号通路，包括配体和细胞功能，不是很了解。这里,我们对斑马鱼的血管生成素和Tie受体进行了全面的突变分析，发现只有angpt1和tie1突变体在躯干淋巴管发育中表现出缺陷。在斑马鱼血管生成素中，只有Angpt1作为配体与Tie1结合。我们间接监测Ang1/Tie1信号并检测出芽内皮细胞（ECs）中的Tie1激活，其中Tie1抑制EGFP-Foxo1a的核进口。Angpt1/Tie1信令函数在EC迁移中，扩散,和早期淋巴管生成过程中的淋巴规范，至少部分通过调节Vegfc/Vegfr3信号。因此，我们显示Angpt1/Tie1信号构成斑马鱼淋巴发育的重要信号通路。
