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 o...淋巴管系统（lymphatic vasculature）是消化系统、免疫系统与循环系统的重要组成部分。同源盒转录因子PROX1对于淋巴管、淋巴管瓣膜（lymphatic valves, LVs）以及淋巴静脉瓣膜（lymphovenous valves, LVVs）的发育至关重要。本团队与其他研究组此前曾报道PROX1与血管内皮生长因子-C（Vascular Endothelial Growth Factor-C, VEGF-C）信号通路之间存在反馈环路。PROX1可促进淋巴管内皮细胞（lymphatic endothelial cells, LECs）中VEGF-C受体VEGFR3的表达；反之，VEGF-C信号通路能够维持淋巴管内皮细胞中PROX1的表达。然而，目前PROX1/VEGF-C反馈环路的分子机制仍不甚明确，且VEGF-C信号通路是否对淋巴管瓣膜与淋巴静脉瓣膜的发育具有必要性也尚未可知。本研究首次证实，VEGF-C信号通路对瓣膜形态发生具有必需作用；同时本研究还发现，转录共激活因子YAP与TAZ可响应VEGF-C信号通路，从而维持淋巴管瓣膜与淋巴静脉瓣膜中PROX1的表达。在淋巴管系统中敲除Yap与Taz后……