Semaphorin3A, Neuropilin-1, and PlexinA1 are required for lymphatic valve formation.
BACKGROUND
The lymphatic vasculature plays a major role in fluid homeostasis, absorption of dietary lipids, and immune surveillance. Fluid transport depends on the presence of intraluminal valves within lymphatic collectors. Defective formation of lymphatic valves leads to lymphedema, a progressive and debilitating condition for which curative treatments are currently unavailable. How lymphatic valve formation is regulated remains largely unknown.


OBJECTIVE
We investigated if the repulsive axon guidance molecule Semaphorin3A (Sema3A) plays a role in lymphatic valve formation.


RESULTS
We show that Sema3A mRNA is expressed in lymphatic vessels and that Sema3A protein binds to lymphatic valves expressing the Neuropilin-1 (Nrp1) and PlexinA1 receptors. Using mouse knockout models, we show that Sema3A is selectively required for lymphatic valve formation, via interaction with Nrp1 and PlexinA1. Sema3a(-/-) mice exhibit defects in lymphatic valve formation, which are not due to abnormal lymphatic patterning or sprouting, and mice carrying a mutation in the Sema3A binding site of Nrp1, or deficient for Plxna1, develop lymphatic valve defects similar to those seen in Sema3a(-/-) mice.


CONCLUSIONS
Our data demonstrate an essential direct function of Sema3A-Nrp1-PlexinA1 signaling in lymphatic valve formation.
CIRB Collège de France/CNRS UMR 7241/INSERM U1050, Paris, France.
Karine
K
Bouvrée
Isabelle
I
Brunet
Raquel
R
Del Toro
Emma
E
Gordon
Claudia
C
Prahst
Brunella
B
Cristofaro
Thomas
T
Mathivet
Yunling
Y
Xu
Jihane
J
Soueid
Vitor
V
Fortuna
Nayoki
N
Miura
Marie-Stéphane
MS
Aigrot
Charlotte H
CH
Maden
Christiana
C
Ruhrberg
Jean Léon
JL
Thomas
Anne
A
Eichmann
D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D042601:Lymphatic Vessels / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D039942:Neuropilin-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D040121:Semaphorin-3A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
D057134:Antibodies, Neutralizing; D001426:Bacterial Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; C492116:PLXNA1 protein, human; C492114:Plxna1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C108639:SEMA3A protein, human; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; C054562:yellow fluorescent protein, Bacteria; D039942:Neuropilin-1; D040321:Vascular Endothelial Growth Factor Receptor-3