Dachsous1-Fat4 Signaling Controls Endothelial Cell Polarization During Lymphatic Valve Morphogenesis-Brief Report.

TitleDachsous1-Fat4 Signaling Controls Endothelial Cell Polarization During Lymphatic Valve Morphogenesis-Brief Report.
Publication TypeJournal Article
Year of Publication2017
AuthorsPujol, F, Hodgson, T, Martinez-Corral, I, Prats, A-C, Devenport, D, Takeichi, M, Genot, E, Mäkinen, T, Francis-West, P, Garmy-Susini, B, Tatin, F
JournalArterioscler Thromb Vasc Biol
Date Published2017 Sep
KeywordsActin Cytoskeleton, Actins, Animals, Cadherins, Cell Movement, Cells, Cultured, Craniofacial Abnormalities, Endothelial Cells, Endothelium, Lymphatic, Fluorescent Antibody Technique, Genetic Predisposition to Disease, Green Fluorescent Proteins, Homeodomain Proteins, Humans, Lymphangiectasis, Intestinal, Lymphangiogenesis, Lymphatic Vessels, Lymphedema, Mice, Knockout, Mutation, Phenotype, Protein Multimerization, Signal Transduction, Transfection, Tumor Suppressor Proteins

<p><b>OBJECTIVE: </b>The purpose of this study was to investigate the role of Fat4 and Dachsous1 signaling in the lymphatic vasculature.</p><p><b>APPROACH AND RESULTS: </b>Phenotypic analysis of the lymphatic vasculature was performed in mice lacking functional or . The overall architecture of lymphatic vasculature is unaltered, yet both genes are specifically required for lymphatic valve morphogenesis. Valve endothelial cells (Prox1 [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.</p><p><b>CONCLUSIONS: </b>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.</p>

Alternate JournalArterioscler Thromb Vasc Biol
PubMed ID28705793
Grant ListSP/13/5/30288 / BHF_ / British Heart Foundation / United Kingdom
R01 AR066070 / AR / NIAMS NIH HHS / United States