EHD2 modulates Dll4 endocytosis during blood vessel development.
EHD2 modulates Dll4 endocytosis during blood vessel development.
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DOI：
10.1111/micc.12740
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发表时间：
2022-01
期刊：
影响因子：
2.4
通讯作者：
Kushner, Erich J.
中科院分区：
文献类型：
--
作者：
Webb, Amelia M.;Francis, Caitlin R.;Judson, Rachael J.;Kincross, Hayle;Lundy, Keanna M.;Westhoff, Dawn E.;Meadows, Stryder M.;Kushner, Erich J.
关键词：
尽管在早期血管发育过程中Delta/Notch信号绝对需要激活侧抑制，但许多机制仍然不清楚该系统如何调节。我们的目的是确定在Notch激活期间Epsin 15同源结构域包含2（EHD 2）参与δ样配体4（Dll 4）内吞。使用体内和体外模型，我们证明EHD 2是一种新的调节剂Notch激活内皮细胞通过控制Dll 4的内吞作用。在体外，EHD 2定位于质膜结合的Dll 4和小窝。小窝复合物的化学破坏导致EHD 2未能围绕Dll 4组织以及Dll 4内化的损失。减少Dll 4内化钝化内皮细胞中的Notch活化。在体内，EHD 2主要在血管系统中表达，与连接标记物VE-钙粘蛋白和Dll 4共定位。敲除斑马鱼中的EHD 2在发育过程中产生了斑马鱼体间血管中畸形芽的显著增加和下游Notch信号的减少。总的来说，我们证明EHD 2是Dll 4转胞吞和下游Notch激活所必需的。
Despite the absolute requirement of Delta/Notch signaling to activate lateral inhibition during early blood vessel development, many mechanisms remain unclear about how this system is regulated. Our objective was to determine the involvement of Epsin 15 Homology Domain Containing 2 (EHD2) in delta‐like ligand 4 (Dll4) endocytosis during Notch activation. Using both in vivo and in vitro models, we demonstrate that EHD2 is a novel modulator of Notch activation in endothelial cells through controlling endocytosis of Dll4. In vitro, EHD2 localized to plasma membrane‐bound Dll4 and caveolae. Chemical disruption of caveolae complexes resulted in EHD2 failing to organize around Dll4 as well as loss of Dll4 internalization. Reduced Dll4 internalization blunted Notch activation in endothelial cells. In vivo, EHD2 is primarily expressed in the vasculature, colocalizing with junctional marker VE‐cadherin and Dll4. Knockout of EHD2 in zebrafish produced a significant increase in dysmorphic sprouts in zebrafish intersomitic vessels during development and a reduction in downstream Notch signaling. Overall, we demonstrate that EHD2 is necessary for Dll4 transcytosis and downstream Notch activation.
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