Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling
Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling
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DOI：
10.1128/mcb.01600-06
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发表时间：
2007-06-01
影响因子：
5.3
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Taniguchi, Koji;Kohno, Ri-ichiro;Yoshimura, Akihiko
Spred/Sprouty家族蛋白负调节生长因子诱导的ERK激活。虽然已经使用基因破坏小鼠研究了Spred-1和Spred-2的个体生理作用，但Spred-1和Spred-2的重叠功能尚未阐明。在这里，我们证明，Spred-1和Spred-2的删除导致胚胎死亡，在胚胎天12.5至15.5，有显着的皮下出血，水肿，和扩张的淋巴管充满红细胞。这种表型类似于Syk（-/-）和SLP-76（-/-）小鼠的表型，这些小鼠在淋巴管与血管分离方面存在缺陷。与WT胚胎相比，Spred-1/2缺陷胚胎LYVE-/-阳性淋巴管和淋巴管内皮细胞数量显著增加，而血管数量无差异。离体集落测定显示，Spred-1/2抑制淋巴管内皮细胞增殖和/或分化。在培养的细胞中，Spred-1或Spred-2的过表达强烈抑制血管内皮生长因子-C（VEGF-C）/WGF受体（VEGFR）-3介导的ERK激活，而Spred-1/2缺陷细胞对VEGFR-3信号极其敏感。这些数据表明，Spread通过负调节VEGF-C/VEGFR-3信号传导在淋巴管发育中起重要作用。
Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk(-/-) and SLP-76(-/-) mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-/- positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/WGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling.