近日,，《生物化學(xué)雜志》（Journal of Biological Chemistry）在線發(fā)表了中科院上海生科院營養(yǎng)所陳雁研究組的最新研究進(jìn)展：“The RAS guanyl nucleotide-releasing protein RasGRP1 is involved in lymphatic development in zebrafish”，揭示了斑馬魚淋巴管發(fā)育過程中的一個關(guān)鍵基因,。
RasGRP1是鳥嘌呤交換因子家族的一員,，是一個Ras的激活蛋白，以往的研究發(fā)現(xiàn)RasGRP1在T淋巴細(xì)胞的分化以及B淋巴細(xì)胞的增殖過程中起著關(guān)鍵的作用,。陳雁研究員領(lǐng)銜的研究組在前期的研究工作中發(fā)現(xiàn)PAQR家族的成員PAQR10和PAQR11能在空間上調(diào)控Ras信號通路,，并且發(fā)現(xiàn)這一調(diào)控過程是由RasGRP1介導(dǎo)的。同時,，在PAQR10/11研究過程中,，研究組成員意外地發(fā)現(xiàn)RasGPR1能夠影響斑馬魚淋巴管的發(fā)育。在這一研究中,，博士生黃恒等人用斑馬魚作為動物模型深入研究了RasGRP1在淋巴管發(fā)育過程中的功能以及機(jī)制,。研究發(fā)現(xiàn)，在斑馬魚胚胎中敲減RasGRP1能夠?qū)е掳唏R魚淋巴管的發(fā)育缺陷,，主要是胸導(dǎo)管（thoracic duct）發(fā)育缺陷,，伴隨著心包膜以及身體軀干位置的淋巴水腫。進(jìn)一步研究發(fā)現(xiàn),，胸導(dǎo)管發(fā)育的缺陷是由于血管二次出芽過程中靜脈出芽所占比例增多,，而淋巴管出芽所占比例減少導(dǎo)致的。外源表達(dá)持續(xù)激活的Ras能夠緩解RasGRP1敲減引起的表型,。另外還發(fā)現(xiàn)同時敲減RasGRP1和血管內(nèi)皮生長因子受體Vegfr3協(xié)同導(dǎo)致胸導(dǎo)管發(fā)育缺陷,。該研究首次揭示了RasGRP1在斑馬魚淋巴管發(fā)育過程中的作用，同時為Ras信號在淋巴管發(fā)育中的研究提供了新的線索,。
該項研究受到中科院,、國家基金委和科技部項目的支持。(生物谷Bioon.com)
DOI:10.1074/jbc.M112.418202
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PMID:
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.
