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

Development. 2020 Dec 13;147(23):dev195453. doi: 10.1242/dev.195453.


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 and TAZ as a crucial molecular pathway in valve development.

Keywords: Lymphovenous valves; PROX1; TAZ; VEGF-C; Valves; YAP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Cell Cycle Proteins / genetics*
  • Embryo, Mammalian
  • Embryonic Development / genetics
  • Gene Expression Regulation, Developmental / genetics
  • Homeodomain Proteins / genetics*
  • Humans
  • Lymphangiogenesis / genetics*
  • Lymphatic Vessels / cytology
  • Lymphatic Vessels / metabolism
  • Mice
  • Morphogenesis / genetics
  • Signal Transduction / genetics
  • Trans-Activators / genetics*
  • Tumor Suppressor Proteins / genetics*
  • Vascular Endothelial Growth Factor C / genetics*
  • Venous Valves / growth & development
  • Venous Valves / metabolism
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Homeodomain Proteins
  • Trans-Activators
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor C
  • Wwtr1 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • prospero-related homeobox 1 protein
  • vascular endothelial growth factor C, mouse