The RAS guanyl nucleotide-releasing protein RasGRP1 is involved in lymphatic development in zebrafish
- Authors
- Huang, H., Jin, T., Wang, L., Wang, F., Zhang, R., Pan, Y., Wang, Z., and Chen, Y.
- ID
- ZDB-PUB-121206-7
- Date
- 2013
- Source
- The Journal of biological chemistry 288(4): 2355-2364 (Journal)
- Registered Authors
- Keywords
- development, lymphangiogenesis, ras, vascular biology, vascular endothelial growth factor (VEGF), zebrafish, PAQR10, RasGRP1
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- DNA-Binding Proteins/chemistry
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/physiology*
- Gene Expression Profiling
- Gene Expression Regulation, Developmental*
- Green Fluorescent Proteins/metabolism
- Guanine Nucleotide Exchange Factors/genetics
- Guanine Nucleotide Exchange Factors/physiology*
- In Situ Hybridization
- Lymphangiogenesis
- Lymphatic System/embryology*
- Lymphatic Vessels/physiology
- Neovascularization, Physiologic
- Thoracic Duct/embryology
- Time Factors
- Vascular Endothelial Growth Factor A/metabolism
- Zebrafish
- ras Proteins/metabolism*
- PubMed
- 23184941 Full text @ J. Biol. Chem.
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.