An Evolutionarily Conserved Role for Polydom/Svep1 During Lymphatic Vessel Formation.
An Evolutionarily Conserved Role for Polydom/Svep1 During Lymphatic Vessel Formation.
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DOI：
10.1161/circresaha.116.308813
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发表时间：
2017-04-14
影响因子：
20.1
通讯作者：
Schulte-Merker S
中科院分区：
文献类型：
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作者：
Karpanen T;Padberg Y;van de Pavert SA;Dierkes C;Morooka N;Peterson-Maduro J;van de Hoek G;Adrian M;Mochizuki N;Sekiguchi K;Kiefer F;Schulte D;Schulte-Merker S
补充数字内容可在文本中找到。淋巴管的形成和功能是一个重要的生理和病理生理过程，但其遗传控制尚不清楚。在这里，我们发现分泌的Polydom/Svep1蛋白对淋巴血管的形成至关重要。我们分析了小鼠和斑马鱼的突变体，以深入了解Polydom/Svep1在淋巴管生成过程中的作用。斑马鱼polydom/svep1突变体的表型分析显示，静脉和淋巴静脉发芽减少，导致节段间动脉数量增加。原始淋巴细胞数量减少，分布在水平肌隔区，但不能向背侧或腹侧迁移，导致淋巴干血管系统严重减少。小鼠Polydom/Svep1基因的相应突变体在E10.5时显示主静脉中Prox-1+细胞的正常输出，但在E12.5时，主静脉与淋巴内皮细胞在第一淋巴静脉接触部位的紧密联系出现异常。此外，E18.5的肠系膜淋巴结构在突变体中没有发生重塑事件，并且缺乏淋巴阀。在鱼和小鼠胚胎中，该基因的表达表明了一种非内皮和非细胞自主机制。我们的数据确定斑马鱼和小鼠Polydom/Svep1是淋巴管生成的必需细胞外因子。斑马鱼的发芽和迁移事件以及小鼠胚胎的淋巴腔内瓣膜的重塑事件都需要间充质细胞与静脉和淋巴内皮细胞密切接触来表达各自的基因。
Supplemental Digital Content is available in the text. Lymphatic vessel formation and function constitutes a physiologically and pathophysiologically important process, but its genetic control is not well understood. Here, we identify the secreted Polydom/Svep1 protein as essential for the formation of the lymphatic vasculature. We analyzed mutants in mice and zebrafish to gain insight into the role of Polydom/Svep1 in the lymphangiogenic process. Phenotypic analysis of zebrafish polydom/svep1 mutants showed a decrease in venous and lymphovenous sprouting, which leads to an increased number of intersegmental arteries. A reduced number of primordial lymphatic cells populated the horizontal myoseptum region but failed to migrate dorsally or ventrally, resulting in severe reduction of the lymphatic trunk vasculature. Corresponding mutants in the mouse Polydom/Svep1 gene showed normal egression of Prox-1+ cells from the cardinal vein at E10.5, but at E12.5, the tight association between the cardinal vein and lymphatic endothelial cells at the first lymphovenous contact site was abnormal. Furthermore, mesenteric lymphatic structures at E18.5 failed to undergo remodeling events in mutants and lacked lymphatic valves. In both fish and mouse embryos, the expression of the gene suggests a nonendothelial and noncell autonomous mechanism. Our data identify zebrafish and mouse Polydom/Svep1 as essential extracellular factors for lymphangiogenesis. Expression of the respective genes by mesenchymal cells in intimate proximity with venous and lymphatic endothelial cells is required for sprouting and migratory events in zebrafish and for remodeling events of the lymphatic intraluminal valves in mouse embryos.