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VEGFA signaling controls physiological and pathological angiogenesis and hematopoiesis. Although many context-dependent signaling pathways downstream of VEGFA have been uncovered,  vegfa  transcriptional regulation in vivo remains unclear. Here, we show that the ETS transcription factor, Etv6, positively regulates  vegfa  expression during  Xenopus  blood stem cell development through multiple transcriptional inputs. In agreement with its established repressive functions, Etv6 directly inhibits expression of the repressor  foxo3 , to prevent Foxo3 from binding to and repressing the  vegfa  promoter. Etv6 also directly activates expression of the activator  klf4 ; reflecting a genome-wide paucity in ETS-binding motifs in Etv6 genomic targets, Klf4 then recruits Etv6 to the  vegfa  promoter to activate its expression. These two mechanisms (double negative gate and feed-forward loop) are classic features of gene regulatory networks specifying cell fates. Thus, Etv6’s dual function, as a transcriptional repressor and activator, controls a major signaling pathway involved in endothelial and blood development in vivo.

Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos