Journal
BLOOD
Volume 123, Issue 7, Pages 1102-1112Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-04-495432
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Funding
- Cancer Council Queensland [APP1008392]
- National Health and Medical Research Council [APP1048242, APP1011242]
- Australian Research Council [FT100100165, FT110100496, FF0776096]
- Australian Research Council [FF0776096, FT100100165, FT110100496] Funding Source: Australian Research Council
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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.
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