Hyaluronic acid receptor Stabilin-2 regulates Erk phosphorylation and arterial--venous differentiation in zebrafish.
Hyaluronic acid receptor Stabilin-2 regulates Erk phosphorylation and arterial--venous differentiation in zebrafish.
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DOI：
10.1371/journal.pone.0088614
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sumanas S
中科院分区：
文献类型：
--
作者：
Rost MS;Sumanas S
内吞作用的透明质酸受体稳定蛋白-2/HARE介导多种糖胺聚糖从血管和淋巴循环中的全身清除。此外，最近的体外研究表明，Stab 2可以通过与透明质酸（HA）相互作用参与信号转导，从而导致Erk磷酸化。然而，尚不清楚Stab 2功能或HA-Stab 2信号传导是否在胚胎发育中发挥任何作用。在这里，我们表明，Stab 2功能的信号转导途径调节动脉-静脉分化在斑马鱼胚胎发育。Stab 2吗啉代敲除胚胎（morphant）显示不存在节段间血管和轴向血管形成缺陷。此外，Stab 2变形子显示动脉-静脉分化的缺陷，包括静脉标志物表达的扩展。同时敲低稳定蛋白-2和Has 2（一种HA合成酶）导致协同效应，认为HA和Stab 2在脉管系统形成期间相互作用。Stab 2 morphant显示动脉祖细胞中Erk磷酸化减少，这是VEGF信号传导的已知转导物，先前与动脉-静脉分化相关。此外，VEGF信号传导作为负反馈环来抑制stab 2表达。这些结果表明，Stab 2参与了一种新的信号通路，在调节Erk磷酸化和建立动脉-静脉身份中起着重要作用。
The hyaluronic acid receptor for endocytosis Stabilin-2/HARE mediates systemic clearance of multiple glycosaminoglycans from the vascular and lymphatic circulations. In addition, recent in vitro studies indicate that Stab2 can participate in signal transduction by interacting with hyaluronic acid (HA), which results in Erk phosphorylation. However, it is not known whether Stab2 function or HA-Stab2 signaling play any role in embryonic development. Here we show that Stab2 functions in a signal transduction pathway regulating arterial-venous differentiation during zebrafish embryogenesis. Stab2 morpholino knockdown embryos (morphants) display an absence of intersegmental vessels and defects in the axial vessel formation. In addition, Stab2 morphants show defects in arterial-venous differentiation including the expansion of venous marker expression. Simultaneous knockdown of Stabilin-2 and Has2, an HA synthetase, results in a synergistic effect, arguing that HA and Stab2 interact during vasculature formation. Stab2 morphants display reduced Erk phosphorylation in the arterial progenitors, which is a known transducer of VEGF signaling, previously associated with arterial-venous differentiation. In addition, VEGF signaling acts as a negative feedback loop to repress stab2 expression. These results argue that Stab2 is involved in a novel signaling pathway that plays an important role in regulating Erk phosphorylation and establishing arterial-venous identity.
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