Complementary Wnt Sources Regulate Lymphatic Vascular Development via PROX1-Dependent Wnt/β-Catenin Signaling.
Complementary Wnt Sources Regulate Lymphatic Vascular Development via PROX1-Dependent Wnt/β-Catenin Signaling.
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DOI：
10.1016/j.celrep.2018.09.049
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发表时间：
2018-10-16
期刊：
影响因子：
8.8
通讯作者：
Srinivasan RS
中科院分区：
文献类型：
--
作者：
Cha B;Geng X;Mahamud MR;Zhang JY;Chen L;Kim W;Jho EH;Kim Y;Choi D;Dixon JB;Chen H;Hong YK;Olson L;Kim TH;Merrill BJ;Davis MJ;Srinivasan RS
WnT/β-连环蛋白信号转导通路是淋巴管发育所必需的。振荡切应力增强淋巴管内皮细胞Wnt/β-catenin信号转导，诱导淋巴水肿相关转录因子GATA2和FOXC2的表达。然而，Oss调控Wnt/β-catenin信号转导及GATA2和FOXC2表达的机制尚不清楚。我们发现Oss在体外激活晶状体上皮细胞自分泌的Wnt/β-catenin信号。Wnless的组织特异性缺失是Wnt配体分泌所必需的，这表明LECs和血管平滑肌细胞是Wnt配体的补充来源，在体内调节淋巴管的发育。此外，LEC主转录因子PROX1与β-catenin和Tcf/Lef转录因子TCF7L1形成复合体，增强Wnt/β-catenin信号转导，促进FOXC2和GATA2在LEC中的表达。因此，我们的工作定义了WNT来源，揭示了PROX1作为WNT信号成分来指导细胞命运，并剖析了PROX1和WNT协同作用的机制。Cha等人。证明淋巴管的发育受淋巴管内皮细胞(LECs)和血管平滑肌细胞分泌的Wnt配体调节。振荡切应力调节晶状体上皮细胞分泌Wnt。PROX1与β-连环蛋白和TCF7L1相互作用，调节Wnt信号，促进FOXC2和GATA2的表达。
Wnt/β-catenin signaling is necessary for lymphatic vascular development. Oscillatory shear stress (OSS) enhances Wnt/β-catenin signaling in cultured lymphatic endothelial cells (LECs) to induce expression of the lymphedema-associated transcription factors GATA2 and FOXC2. However, the mechanisms by which OSS regulates Wnt/β-catenin signaling and GATA2 and FOXC2 expression are unknown. We show that OSS activates autocrine Wnt/β-catenin signaling in LECs in vitro. Tissue-specific deletion of Wntless, which is required for the secretion of Wnt ligands, reveals that LECs and vascular smooth muscle cells are complementary sources of Wnt ligands that regulate lymphatic vascular development in vivo. Further, the LEC master transcription factor PROX1 forms a complex with β-catenin and the TCF/LEF transcription factor TCF7L1 to enhance Wnt/β-catenin signaling and promote FOXC2 and GATA2 expression in LECs. Thus, our work defines Wnt sources, reveals that PROX1 directs cell fate by acting as a Wnt signaling component, and dissects the mechanisms of PROX1 and Wnt synergy. Cha et al. demonstrate that lymphatic vascular development is regulated by Wnt ligands secreted by lymphatic endothelial cells (LECs) and vascular smooth muscle cells. Oscillatory shear stress regulates Wnt secretion from LECs. PROX1 interacts with β-catenin and TCF7L1 to regulate Wnt signaling and promote the expression of FOXC2 and GATA2.
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