Vegfc Regulates Bipotential Precursor Division and Prox1 Expression to Promote Lymphatic Identity in Zebrafish

Lymphatic vessels arise chiefly from preexisting embryonic veins. Genetic regulators of lymphatic fate are known, but how dynamic cellular changes contribute during the acquisition of lymphatic identity is not understood. We report the visualization of zebrafish lymphatic precursor cell dynamics during fate restriction. In the cardinal vein, cellular commitment is linked with the division of bipotential Prox1-positive precursor cells, which occurs immediately prior to sprouting angiogenesis. Following precursor division, identities are established asymmetrically in daughter cells; one daughter cell becomes lymphatic and progressively upregulates Prox1, and the other downregulates Prox1 and remains in the vein. Vegfc drives cell division and Prox1 expression in lymphatic daughter cells, coupling signaling dynamics with daughter cell fate restriction and precursor division. [Display omitted] •Prox1 expression initiates in the zebrafish vein before secondary angiogenesis•Prox1 is essential for lymphangiogenesis in zebrafish•Bipotential precursors divide to generate venous and lymphatic endothelial cells•Vegfc concomitantly drives bipotential precursor division and Prox1 expression Using live imaging, Koltowska and Lagendijk et al. identify bipotential Prox1-expressing precursor cells that divide to generate daughter cells with distinct identities. Following Vegfc-driven cell division, a venous daughter cell remains in the vein and a lymphatic daughter cell leaves, a process by which one vascular lineage derives from another.