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The homeobox gene  Prox1  is crucial for mammalian lymphatic vascular development. In the absence of Prox1, lymphatic endothelial cells (LECs) are not specified. The maintenance of LEC identity also requires the constant expression of Prox1. However, the mechanisms controlling the expression of this gene in LECs remain poorly understood. The SRY-related gene  Sox18  is required to induce Prox1 expression in venous LEC progenitors. Although  Sox18  is also expressed in embryonic arteries, these vessels do not express Prox1, nor do they give rise to LECs. This finding suggests that some venous endothelial cell-specific factor is required for the activation of  Prox1 . Here we demonstrate that the nuclear hormone receptor Coup-TFII is necessary for the activation of  Prox1  in embryonic veins by directly binding a conserved DNA domain in the regulatory region of  Prox1 . In addition, we show that the direct interaction between nuclear hormone receptors and Prox1 is also necessary for the maintenance of  Prox1  expression during early stages of LEC specification and differentiation.

The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells