An Evolutionarily Conserved Role for Polydom/Svep1 During Lymphatic Vessel Formation.
BACKGROUND
Lymphatic vessel formation and function constitutes a physiologically and pathophysiologically important process, but its genetic control is not well understood.


OBJECTIVE
Here, we identify the secreted Polydom/Svep1 protein as essential for the formation of the lymphatic vasculature. We analyzed mutants in mice and zebrafish to gain insight into the role of Polydom/Svep1 in the lymphangiogenic process.


RESULTS
Phenotypic analysis of zebrafishpolydom/svep1mutants showed a decrease in venous and lymphovenous sprouting, which leads to an increased number of intersegmental arteries. A reduced number of primordial lymphatic cells populated the horizontal myoseptum region but failed to migrate dorsally or ventrally, resulting in severe reduction of the lymphatic trunk vasculature. Corresponding mutants in the mousePolydom/Svep1gene showed normal egression of Prox-1+cells from the cardinal vein at E10.5, but at E12.5, the tight association between the cardinal vein and lymphatic endothelial cells at the first lymphovenous contact site was abnormal. Furthermore, mesenteric lymphatic structures at E18.5 failed to undergo remodeling events in mutants and lacked lymphatic valves. In both fish and mouse embryos, the expression of the gene suggests a nonendothelial and noncell autonomous mechanism.


CONCLUSIONS
Our data identify zebrafish and mouse Polydom/Svep1 as essential extracellular factors for lymphangiogenesis. Expression of the respective genes by mesenchymal cells in intimate proximity with venous and lymphatic endothelial cells is required for sprouting and migratory events in zebrafish and for remodeling events of the lymphatic intraluminal valves in mouse embryos.
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.). schultes@ukmuenster.de Terhi.Karpanen@rr-research.no.
Terhi
T
Karpanen
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Yvonne
Y
Padberg
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Serge A
SA
van de Pavert
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Cathrin
C
Dierkes
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Nanami
N
Morooka
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Josi
J
Peterson-Maduro
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Glenn
G
van de Hoek
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Max
M
Adrian
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Naoki
N
Mochizuki
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Kiyotoshi
K
Sekiguchi
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Friedemann
F
Kiefer
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.).
Dörte
D
Schulte
From the Hubrecht Institute, KNAW and UMC Utrecht, Utrecht, the Netherlands (T.K., S.A.v.d.P., J.P.-M., G.v.d.H., M.A., S.S.-M.); Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Germany (Y.P., D.S., S.S.-M.); CiM Cluster of Excellence (EXC 1003-CiM), Münster, Germany (Y.P., D.S., S.S.-M.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (C.D., F.K.); Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Japan (N.M., K.S.); and Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan (N.M.). schultes@ukmuenster.de Terhi.Karpanen@rr-research.no.
Stefan
S
Schulte-Merker
D000818:Animals; D030801:Animals, Genetically Modified; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D002450:Cell Communication; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004729:Endothelium, Lymphatic / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000002:abnormalities / Q000378:metabolism* / Q000503:physiopathology; D008648:Mesoderm / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; C418635:Polydom protein, mouse; D011506:Proteins; C000617888:Svep1 protein, zebrafish; D029961:Zebrafish Proteins
Polydom/Svep1; arteries; lymphangiogenesis; lymphatic vessels; mice; veins; zebrafish