ZFIN ID: ZDB-PUB-160914-3
Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors
Shin, M., Male, I., Beane, T.J., Villefranc, J.A., Kok, F.O., Zhu, L.J., Lawson, N.D.
Date: 2016
Source: Development (Cambridge, England)   143(20): 3785-3795 (Journal)
Registered Authors: Lawson, Nathan, Shin, Masahiro, Villefranc, Jacque
Keywords: Flt4, TALEN, Vegfc, Lymphatic, Zebrafish
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases/genetics
  • Extracellular Signal-Regulated MAP Kinases/metabolism*
  • Gene Expression Regulation, Developmental/genetics
  • Gene Expression Regulation, Developmental/physiology
  • Genotype
  • In Situ Hybridization
  • Lymphatic Vessels/cytology*
  • Lymphatic Vessels/embryology
  • Lymphatic Vessels/metabolism*
  • Mutation/genetics
  • Phosphorylation/genetics
  • Phosphorylation/physiology
  • Signal Transduction/genetics
  • Signal Transduction/physiology
  • Vascular Endothelial Growth Factor C/genetics
  • Vascular Endothelial Growth Factor C/metabolism*
  • Vascular Endothelial Growth Factor Receptor-3/genetics
  • Vascular Endothelial Growth Factor Receptor-3/metabolism
  • Zebrafish/embryology*
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 27621059 Full text @ Development
Vascular endothelial growth factor C (Vegfc) activates its receptor, Flt4, to induce lymphatic development. However, the signals that act downstream of Flt4 in this context in vivo remain unclear. To better understand Flt4 signaling, we generated zebrafish bearing a deletion in the Flt4 cytoplasmic domain that eliminates tyrosines Y1226 and 1227. Embryos bearing this deletion failed to initiate sprouting or differentiation of trunk lymphatic vessels and did not form a thoracic duct. Deletion of Y1226/7 prevented ERK phosphorylation in lymphatic progenitors while ERK inhibition blocked trunk lymphatic sprouting and differentiation. Conversely, endothelial autonomous ERK activation rescued lymphatic sprouting and differentiation in flt4 mutants. Interestingly, embryos bearing the Y1226/7 deletion formed a functional facial lymphatic network enabling them to develop normally to adulthood. By contrast, flt4 null larvae displayed hypoplastic facial lymphatics and severe lymphedema. Thus, facial lymphatic vessels appear to be the first functional lymphatic network in the zebrafish, while the thoracic duct is initially dispensable for lymphatic function. Moreover, distinct signaling pathways downstream of Flt4 govern lymphatic morphogenesis and differentiation in different anatomical locations.