File:LEC specification in the cardinal vein.jpg

English: From around embryonic day 8.5 (E8.5) in mice, Coup-TFII, regulated by BRG1, is expressed in the nucleus of all the endothelial cells of the cardinal vein, promoting venous identity through the inhibition of the Notch pathway. At E9.0 a few cells in the jugular region of the cardinal vein start expressing Sox18. This is initiated by the reduction of an uncharacterized AKT inhibitor that releases AKT to phosphorylate RAF1 at Ser259 initiating a signaling cascade that activates SOX18. Cooperation between COUP-TFII and SOX18 induces PROX1 expression, thus around E9.5, Prox1 can be detected in polarized LEC precursors in the cardinal vein. It is thought that cells of paraxial mesodermal (PXM) origin, rather than lateral plate mesodermal (LPM) origin, locate in the dorsolateral part of the cardinal vein and are the ones able to transdifferentiate through the COUP-TFII/SOX18/PROX1 program. Other key transcription factors like GATA2 and HHEX regulate PROX1 expression. The PROX1-VEGFR3 autoregulatory feedback maintains the identity and the number of lymphatic endothelial cell progenitors.