Transcription factor FOXC2 demarcates the jugular lymphangiogenic region in avian embryos

In the human, mutations of the forkhead winged-helix transcription factor FOXC2 cause the lymphedema-distichiasis syndrome, which is characterized by a double row of eyelashes and pubertal onset lymphedema of the legs due to hyperplasia and malformation of lymphatic collectors. While a function of FOXC2 for the differentiation of lymphatic collectors is well documented, recent studies have indicated an early function for the sprouting of lymphatics from embryonic veins. We studied the expression of FoxC2 in early avian embryos and compared its expression pattern with that of the homeobox transcription factor Prox1, which is essential for lymphatic endothelial cell (LEC) development. We show that FoxC2 demarcates a segment of the somatopleura in the cervical region on embryonic day (ED) 3, before Prox1 is expressed. On ED 4, its expression domain coincides with that of Prox1 in the jugular region. This region is characterized by the confluence of Tie2-positive anterior and posterior cardinal veins. It has been shown that Prox1 expression in a subpopulation of venous endothelial cells induces transdifferentiation into LECs. Our data suggest that FoxC2, in addition to its late functions during lymph collector differentiation, has an early function during lymphendothelial commitment of venous ECs in the jugular region.