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The lymphatic vasculature plays roles in tissue fluid balance, immune cell trafficking, fatty acid absorption, cancer metastasis, and cardiovascular disease. Lymphatic vessels form by lymphangiogenesis, the sprouting of new lymphatics from pre-existing vessels, in both development and disease contexts. The apical signaling pathway in lymphangiogenesis is the VEGFC/VEGFR3 pathway, yet how signaling controls cellular transcriptional output remains unknown. We used a forward genetic screen in zebrafish to identify the transcription factor  mafba  as essential for lymphatic vessel development. We found that  mafba  is required for the migration of lymphatic precursors after their initial sprouting from the posterior cardinal vein.  mafba  expression is enriched in sprouts emerging from veins, and we show that  mafba  functions cell-autonomously during lymphatic vessel development. Mechanistically, Vegfc signaling increases  mafba  expression to control downstream transcription, and this regulatory relationship is dependent on the activity of SoxF transcription factors, which are essential for  mafba  expression in venous endothelium. Here we identify an indispensable Vegfc–SoxF–Mafba pathway in lymphatic development.

mafba is a downstream transcriptional effector of Vegfc signaling essential for embryonic lymphangiogenesis in zebrafish