Complementary Wnt Sources Regulate Lymphatic Vascular Development via PROX1-Dependent Wnt/β-Catenin Signaling

Area of Science:

• Vascular Biology
• Molecular Biology
• Developmental Biology

Background:

• Wnt/β-catenin signaling is crucial for lymphatic vascular development.
• Oscillatory shear stress (OSS) enhances this signaling in lymphatic endothelial cells (LECs), upregulating GATA2 and FOXC2.
• The precise mechanisms linking OSS, Wnt signaling, and transcription factor expression remained unclear.

Purpose of the Study:

• To elucidate the mechanisms by which OSS regulates Wnt/β-catenin signaling in LECs.
• To identify the sources of Wnt ligands involved in lymphatic vascular development.
• To understand the role of PROX1 in Wnt signaling and transcription factor regulation.

Main Methods:

• In vitro studies using cultured LECs to assess Wnt/β-catenin signaling.
• In vivo studies utilizing tissue-specific deletion of Wntless to identify Wnt ligand sources.
• Co-immunoprecipitation and molecular assays to investigate protein complex formation and gene expression.

Main Results:

• OSS was shown to activate autocrine Wnt/β-catenin signaling within LECs.
• LECs and vascular smooth muscle cells were identified as complementary sources of Wnt ligands essential for lymphatic development.
• PROX1 was found to form a complex with β-catenin and TCF7L1, enhancing Wnt signaling and promoting FOXC2 and GATA2 expression.

Conclusions:

• This study defines the sources of Wnt ligands regulating lymphatic vascular development.
• PROX1 acts as a key Wnt signaling component, directing cell fate and promoting GATA2 and FOXC2 expression.
• The synergistic mechanisms between PROX1 and Wnt signaling in LECs were dissected.