YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling

Lymphatic vasculature is an integral part of digestive, immune and
circulatory systems. The homeobox transcription factor PROX1 is necessary
for the development of lymphatic vessels, lymphatic valves (LVs) and
lymphovenous valves (LVVs). We and others previously reported a feedback
loop between PROX1 and Vascular Endothelial Growth Factor-C (VEGF-C)
signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in
lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains
PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback
loop remain poorly understood. Whether VEGF-C signaling is necessary for
LV and LVV development is also unknown. Here, we report for the first time
that VEGF-C signaling is necessary for valve morphogenesis. We have also
discovered that the transcriptional co-activators YAP and TAZ are required
to maintain PROX1 expression in LVs and LVVs in response to VEGF-C
signaling. Deletion of Yap and Taz in the lymphatic vasculature of mouse
embryos did not affect the formation of LVs or LVVs, but resulted in the
degeneration of these structures. Our results have identified
VEGF-C/YAP/TAZ as a critical molecular pathway in valve development.