Complementary Wnt Sources Regulate Lymphatic Vascular Development via PROX1-Dependent Wnt/β-Catenin Signaling
Boksik Cha,
Xin Geng,
Md. Riaj Mahamud,
Jenny Y. Zhang,
Lijuan Chen,
Wantae Kim,
Eek-hoon Jho,
Yeunhee Kim,
Dongwon Choi,
J. Brandon Dixon,
Hong Chen,
Young-Kwon Hong,
Lorin Olson,
Tae Hoon Kim,
Bradley J. Merrill,
Michael J. Davis,
R. Sathish Srinivasan
Affiliations
Boksik Cha
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
Xin Geng
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
Md. Riaj Mahamud
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Jenny Y. Zhang
Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL, USA
Lijuan Chen
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
Wantae Kim
Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Deajeon, Korea
Eek-hoon Jho
Department of Life Science, University of Seoul, Seoul, Korea
Yeunhee Kim
Department of Biological Sciences and Center for Systems Biology, The University of Texas at Dallas, Richardson, TX, USA
Dongwon Choi
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
J. Brandon Dixon
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
Hong Chen
Vascular Biology Program, Boston Children’s Hospital, Boston, MA, USA
Young-Kwon Hong
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Lorin Olson
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Tae Hoon Kim
Department of Biological Sciences and Center for Systems Biology, The University of Texas at Dallas, Richardson, TX, USA
Bradley J. Merrill
Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL, USA
Michael J. Davis
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
R. Sathish Srinivasan
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Corresponding author
Summary: 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. Keywords: lymphatic vasculature, lymphovenous valves, lymphatic valves, PROX1, GATA2, FOXC2, Wnt/β-catenin signaling, oscillatory shear stress, Wntless, TCF7L1
