近日，《生物化学杂志》（Journal of Biological Chemistry）在线发表了中科院上海生科院营养所陈雁研究组的最新研究进展：“The RAS guanyl nucleotide-releasing protein RasGRP1 is involved in lymphatic development in zebrafish”，揭示了斑马鱼淋巴管发育过程中的一个关键基因。
RasGRP1是鸟嘌呤交换因子家族的一员，是一个Ras的激活蛋白，以往的研究发现RasGRP1在T淋巴细胞的分化以及B淋巴细胞的增殖过程中起着关键的作用。陈雁研究员领衔的研究组在前期的研究工作中发现PAQR家族的成员PAQR10和PAQR11能在空间上调控Ras信号通路，并且发现这一调控过程是由RasGRP1介导的。同时，在PAQR10/11研究过程中，研究组成员意外地发现RasGPR1能够影响斑马鱼淋巴管的发育。在这一研究中，博士生黄恒等人用斑马鱼作为动物模型深入研究了RasGRP1在淋巴管发育过程中的功能以及机制。研究发现，在斑马鱼胚胎中敲减RasGRP1能够导致斑马鱼淋巴管的发育缺陷，主要是胸导管（thoracic duct）发育缺陷，伴随着心包膜以及身体躯干位置的淋巴水肿。进一步研究发现，胸导管发育的缺陷是由于血管二次出芽过程中静脉出芽所占比例增多，而淋巴管出芽所占比例减少导致的。外源表达持续激活的Ras能够缓解RasGRP1敲减引起的表型。另外还发现同时敲减RasGRP1和血管内皮生长因子受体Vegfr3协同导致胸导管发育缺陷。该研究首次揭示了RasGRP1在斑马鱼淋巴管发育过程中的作用，同时为Ras信号在淋巴管发育中的研究提供了新的线索。
该项研究受到中科院、国家基金委和科技部项目的支持。(生物谷Bioon.com)
DOI:10.1074/jbc.M112.418202
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The RAS guanyl nucleotide-releasing protein RasGRP1 is involved in lymphatic development in zebrafish
Heng Huang, Ting Jin, Lin Wang, Fulong Wang, Rui Zhang, Yi Pan, Zhenzhen Wang and Yan Chen*
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, while 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 intersegmental vessels was increased, while 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 constitutive 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.
