The RAS Guanyl Nucleotide-releasing Protein RasGRP1 Is Involved in Lymphatic Development in Zebrafish
The RAS Guanyl Nucleotide-releasing Protein RasGRP1 Is Involved in Lymphatic Development in Zebrafish
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RAS鸟苷酸释放蛋白RasGRP1参与斑马鱼的淋巴管发育
DOI：
10.1074/jbc.m112.418202
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发表时间：
2013-01-25
影响因子：
4.8
通讯作者：
Chen, Yan
中科院分区：
文献类型：
--
作者：
Huang, Heng;Jin, Ting;Chen, Yan
淋巴发育的分子基础在很大程度上仍然是未知的。以斑马鱼为模型，我们发现Ras鸟嘌呤释放蛋白1 （RasGRP1）的新作用，Ras鸟嘌呤释放蛋白1参与淋巴管生成中的Ras激活。斑马鱼的第一个淋巴管是胸导管，胸导管由后主静脉产生。在斑马鱼胚胎中注射morpholino敲低rasgrp1会损害胸导管的形成，并伴有心包和导管水肿，而胚胎的血管发育基本未受影响。在rasgrp1敲低的胚胎中，产生副脉淋巴母细胞串的芽的数量减少。同时，次生芽的总数没有变化。结果表明，静脉节段间血管增多，淋巴血管减少。由rasgrp1敲低引起的淋巴发育缺陷可以通过异位表达组成活性的HRas来挽救。进一步分析发现，RasGRP1敲低可与flt4/vegfr3敲低协同诱导淋巴管生成缺陷。综上所述，这一发现证明了RasGRP1在斑马鱼淋巴发育中的关键作用。
The molecular basis of the lymphatic development remains largely unknown. Using zebrafish as a model, we discovered a novel role for the Ras guanine-releasing protein 1 (RasGRP1), a protein involved in Ras activation in lymphangiogenesis. Secondary lymphatic sprouts from the posterior cardinal vein give rise to thoracic duct which is the first lymphatic vessel in zebrafish. Knockdown of rasgrp1 by injecting morpholino in zebrafish embryos impaired formation of thoracic duct accompanied by pericardial and truck edema, whereas blood vessel development of the embryos was largely unaffected. In rasgrp1-knockdown embryos, the number of sprouts producing the string of parachordal lymphangioblast cells was reduced. Meanwhile the total number of the secondary sprouts was not changed. As a result, the number of venous intersegmental vessels was increased, whereas the number of lymphatic vessel was reduced at a later stage. The lymphatic developmental defects caused by rasgrp1 knockdown could be rescued by ectopic expression of a constitutively active HRas. Further analysis revealed that RasGRP1 knockdown could synergize with flt4/vegfr3 knockdown to induce defects in lymphangiogenesis. Taken together, this finding demonstrates a critical role for RasGRP1 in lymphatic development in zebrafish.