The molecular fate-determining network of lymphatic endothelial cells. Lymphatic endothelial cell specification is regulated by a dynamic molecular network of opposing and complementary forces. Notch, COUP-TFII, and Prox-1 are the 3 major players. Activation of Notch signaling suppresses the expression of Prox-1 and COUP-TFII through the action of Hey1/2 in lymphatic endothelial cells. Endogenous Prox-1 and COUP-TFII down-regulate VEGFR-2 and therefore ultimately suppress the expression of VEGF-A. In parallel, Notch signaling displays positive influence on VEGFR-3 and EphrinB2 signaling. SOX18 is also known to be capable of up-regulating Prox-1 in certain conditions. COUP-TF II indicates chicken ovalbumin upstream transcription factor II; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.