English: PROX1 expression leads to the downregulation of blood endothelial markers and the upregulation of vascular endothelial growth factor receptor 3 (VEGFR3) expression. At E10.5, these PROX1- and VEGFR3-expressing LECs (green) separate from the cardinal vein (blue) and migrate dorsally, guided by a molecular gradient of vascular endothelial growth factor C (VEGFC). Platelet aggregation at the points of LEC migration is shown (red). This initial phase of lymphatic expansion is absolutely dependent on VEGFR3-expressing LECs responding to VEGFC. Paracrine CCBE1 secretion at sites of lymphatic vessel growth promotes proteolytic cleavage of pro-VEGFC by the metalloprotease ADAMTS3. This activates and mobilizes a fully mature VEGFC molecule that on binding to VEGFR3 can activate autophosphorylation and downstream signaling. It is thought that CCBE1 binds to the extracellular matrix (ECM) while VEGFC cleavage may occur on the lymphatic endothelial cell surface. Key transcription factors like GATA2 and HHEX regulate VEGFR3 expression and the PROX1-VEGFR3 autoregulatory feedback remains important during the vascular expansion process. At E11.5 primordial lymph sacs are formed. Drawing of a human embryo (at gestational week 6 – 7, head not shown) displaying the first primitive lymphatic structures seen as six primary lymph sacs in green (veins in blue). The jugular lymph sacs develop around the upper jugular vein, the retroperitoneal lymph sac and cisterna chyli in the central segment of the embryo and the two posterior lymph sacs around the lower limbs near the iliac veins.