title: The RAS guanyl nucleotide-releasing protein RasGRP1 is involved in lymphatic development in zebrafish.
abstract: 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.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Huang
authors.forename: Ting
authors.initials: T
authors.lastname: Jin
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Fulong
authors.initials: F
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D017403:In Situ Hybridization; D042583:Lymphangiogenesis; D008208:Lymphatic System / Q000196:embryology*; D042601:Lymphatic Vessels / Q000502:physiology; D018919:Neovascularization, Physiologic; D013897:Thoracic Duct / Q000196:embryology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C491790:RASGRP1 protein, human; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D018631:ras Proteins