Dachsous1–Fat4 Signaling Controls Endothelial Cell Polarization During Lymphatic Valve Morphogenesis—Brief Report

• DOI: 10.1161/atvbaha.117.309818
• Publication Date: 2017-07-14T01:10:34Z
• Authors: Francoise Pujol; Tina Hodgson; Ines Martinez-Corral; Anne-Catherine Prats; Danelle Devenport; Masatoshi Takeichi; Elisabeth Genot; Taija Mäkinen; Philippa Francis-...; Barbara Garmy-Susini; Florence Tatin
• Keywords: 0301 basic medicine; Green Fluorescent Proteins; 610; Fluorescent Antibody Technique; Craniofacial Abnormalities; 03 medical and health sciences; Cell Movement; Animals; Humans; Genetic Predisposition to Disease; Lymphedema; Lymphangiogenesis; Cells, Cultured; Lymphatic Vessels; Homeodomain Proteins; Mice, Knockout; Endothelial Cells; lymphedema; Cadherins; endothelial cells; Actins; lymphangiogenesis; cell polarity; Actin Cytoskeleton; intercellular junctions; Mutation; Endothelium, Lymphatic; Lymphangiectasis, Intestinal

Objective— The purpose of this study was to investigate the role of Fat4 and Dachsous1 signaling in the lymphatic vasculature.

Approach and Results—

Phenotypic analysis of the lymphatic vasculature was performed in mice lacking functional Fat4 or Dachsous1 . The overall architecture of lymphatic vasculature is unaltered, yet both genes are specifically required for lymphatic valve morphogenesis. Valve endothelial cells (Prox1 high [prospero homeobox protein 1] cells) are disoriented and failed to form proper valve leaflets. Using Lifeact-GFP (green fluorescent protein) mice, we revealed that valve endothelial cells display prominent actin polymerization. Finally, we showed the polarized recruitment of Dachsous1 to membrane protrusions and cellular junctions of valve endothelial cells in vivo and in vitro.

Conclusions— Our data demonstrate that Fat4 and Dachsous1 are critical regulators of valve morphogenesis. This study highlights that valve defects may contribute to lymphedema in Hennekam syndrome caused by Fat4 mutations.