Francoise Pujol1, Tina Hodgson1, Ines Martinez-Corral1, Anne-Catherine Prats1, Danelle Devenport1, Masatoshi Takeichi1, Elisabeth Genot1, Taija Mäkinen1, Philippa Francis-West1, Barbara Garmy-Susini1, Florence Tatin2. 1. From the I2MC INSERM UMR 1048, Toulouse Cedex, France (F.P., A.-C.P., B.G.-S., F.T.); Department Craniofacial Development and Stem Cell Biology, King's College London, United Kingdom (T.H., P.F.-W.); Rudbeck Laboratory, Department Immunology, Genetics and Pathology, Uppsala University, Sweden (I.M.-C., T.M.); Department of Molecular Biology, Princeton University, NJ (D.D.); Laboratory for Cell Adhesion and Tissue Patterning, RIKEN Center for Developmental Biology, Kobe, Japan (M.T.); and INSERM, Université de Bordeaux, France (E.G.). 2. From the I2MC INSERM UMR 1048, Toulouse Cedex, France (F.P., A.-C.P., B.G.-S., F.T.); Department Craniofacial Development and Stem Cell Biology, King's College London, United Kingdom (T.H., P.F.-W.); Rudbeck Laboratory, Department Immunology, Genetics and Pathology, Uppsala University, Sweden (I.M.-C., T.M.); Department of Molecular Biology, Princeton University, NJ (D.D.); Laboratory for Cell Adhesion and Tissue Patterning, RIKEN Center for Developmental Biology, Kobe, Japan (M.T.); and INSERM, Université de Bordeaux, France (E.G.). florence.tatin@inserm.fr.
Abstract
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 (Prox1high [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.
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 (Prox1high [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.
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Kelly L Betterman; Drew L Sutton; Genevieve A Secker; Jan Kazenwadel; Anna Oszmiana; Lillian Lim; Naoyuki Miura; Lydia Sorokin; Benjamin M Hogan; Mark L Kahn; Helen McNeill; Natasha L Harvey Journal: J Clin Invest Date: 2020-06-01 Impact factor: 14.808
Authors: Tui Neri; Emilye Hiriart; Patrick P van Vliet; Emilie Faure; Russell A Norris; Batoul Farhat; Bernd Jagla; Julie Lefrancois; Yukiko Sugi; Thomas Moore-Morris; Stéphane Zaffran; Randolph S Faustino; Alexander C Zambon; Jean-Pierre Desvignes; David Salgado; Robert A Levine; Jose Luis de la Pompa; André Terzic; Sylvia M Evans; Roger Markwald; Michel Pucéat Journal: Nat Commun Date: 2019-04-26 Impact factor: 14.919