Dachsousl-Fat4 Signaling Controls Endothelial Cell Polarization During Lymphatic Valve Morphogenesis-Brief Report
Dachsousl-Fat4 Signaling Controls Endothelial Cell Polarization During Lymphatic Valve Morphogenesis-Brief Report
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DOI：
10.1161/atvbaha.117.309818
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发表时间：
2017-09-01
影响因子：
8.7
通讯作者：
Tatin, Florence
中科院分区：
文献类型：
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作者：
Pujol, Francoise;Hodgson, Tina;Tatin, Florence
目的：探讨Fat4和Dachsous 1信号在淋巴血管中的作用。方法与结果：对功能性Fat4或Dachsousl缺失小鼠的淋巴血管进行表型分析。淋巴血管的整体结构是不变的，但这两个基因是特别需要的淋巴阀形态发生。瓣膜内皮细胞（Proxl(high) [prospero homobox protein 1]细胞）定向不清，无法形成合适的瓣膜小叶。使用Lifeact-GFP（绿色荧光蛋白）小鼠，我们发现瓣膜内皮细胞表现出明显的肌动蛋白聚合。最后，我们在体内和体外实验中显示了Dachsousl在瓣膜内皮细胞的膜突起和细胞连接处的极化招募。结论：我们的数据表明Fat4和Dachsousl是瓣膜形态发生的关键调节因子。本研究强调瓣膜缺陷可能导致由Fat4突变引起的Hennekam综合征淋巴水肿。
Objective-The purpose of this study was to investigate the role of Fat4 and Dachsous 1 signaling in the lymphatic vasculature.Approach and Results-Phenotypic analysis of the lymphatic vasculature was performed in mice lacking functional Fat4 or Dachsousl. The overall architecture of lymphatic vasculature is unaltered, yet both genes are specifically required for lymphatic valve morphogenesis. Valve endothelial cells (Proxl(high) [prospero homeobox protein 1] cells) are disoriented and failed to form proper valve leaflets. Using Lifeact-GFP (green fluorescent protein) mice, we revealed that valve endothelial cells display prominent actin polymerization. Finally, we showed the polarized recruitment of Dachsousl to membrane protrusions and cellular junctions of valve endothelial cells in vivo and in vitro.Conclusions-Our data demonstrate that Fat4 and Dachsousl are critical regulators of valve morphogenesis. This study highlights that valve defects may contribute to lymphedema in Hennekam syndrome caused by Fat4 mutations.