title: VEGFD regulates blood vascular development by modulating SOX18 activity.
abstract: Vascular endothelial growth factor-D (VEGFD) is a potent pro-lymphangiogenic molecule during tumor growth and is considered a key therapeutic target to modulate metastasis. Despite roles in pathological neo-lymphangiogenesis, the characterization 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-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase signaling 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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia;
authors.forename: Tam
authors.initials: T
authors.lastname: Duong
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Koltowska
authors.forename: Cathy
authors.initials: C
authors.lastname: Pichol-Thievend
authors.forename: Ludovic
authors.initials: L
authors.lastname: Le Guen
authors.forename: Frank
authors.initials: F
authors.lastname: Fontaine
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Smith
authors.forename: Vy
authors.initials: V
authors.lastname: Truong
authors.forename: Renae
authors.initials: R
authors.lastname: Skoczylas
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Hogan
authors.forename: Mathias
authors.initials: M
authors.lastname: Francois
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001808:Blood Vessels / Q000196:embryology*; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics*; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042643:Vascular Endothelial Growth Factor D / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D055760:SOXF Transcription Factors; C526282:Sox18 protein, zebrafish; D042643:Vascular Endothelial Growth Factor D; D029961:Zebrafish Proteins