ZFIN ID: ZDB-PUB-140108-18
VEGFD regulates blood vascular development by modulating SOX18 activity
Duong, T., Koltowska, K., Pichol-Thievend, C., Le Guen, L., Fontaine, F., Smith, K.A., Truong, V., Skoczylas, R., Stacker, S.A., Achen, M.G., Koopman, P., Hogan, B.M., and Francois, M.
Date: 2014
Source: Blood   123(7): 1102-12 (Journal)
Registered Authors: Hogan, Ben M., Le Guen, Ludovic, Smith, Kelly
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Blood Vessels/embryology*
  • Embryo, Mammalian
  • Embryo, Nonmammalian
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks/genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic/genetics*
  • SOXF Transcription Factors/genetics
  • SOXF Transcription Factors/metabolism*
  • Vascular Endothelial Growth Factor D/physiology*
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 24269955 Full text @ Blood

Vascular endothelial growth factor-D (VEGFD) is a potent pro-lymphangiogenic molecule of tumour growth and is considered a key therapeutic target to modulate metastasis. Despite roles in pathological neo-lymphangiogenesis, the characterisation of an endogenous role for VEGFD in vascular development has remained elusive. Here, we used zebrafish to assay for genetic interactions between the Vegf/Vegf-receptor pathway and SoxF transcription factors and identified a specific interaction between Vegfd and Sox18. Double knockdown zebrafish embryos for Sox18/Vegfd and Sox7/Vegfd exhibit defects in arteriovenous differentiation. Supporting this observation, we found that Sox18/Vegfd double but not single knockout mice displayed dramatic vascular development defects. We find that VEGFD-MEK-ERK signalling modulates SOX18-mediated transcription, functioning at least in part by enhancing nuclear concentration and transcriptional activity in vascular endothelial cells. This work suggests that VEGFD-mediated pathologies include or involve an underlying dysregulation of SOXF-mediated transcriptional networks.