The Wnt signaling regulator R-spondin 3 promotes angioblast and vascular development.
The vertebrate embryonic vasculature develops from angioblasts, which are specified from mesodermal precursors and develop in close association with blood cells. The signals that regulate embryonic vasculogenesis and angiogenesis are incompletely understood. Here, we show that R-spondin 3 (Rspo3), a member of a novel family of secreted proteins in vertebrates that activate Wnt/beta-catenin signaling, plays a key role in these processes. In Xenopus embryos, morpholino antisense knockdown of Rspo3 induces vascular defects because Rspo3 is essential for regulating the balance between angioblast and blood cell specification. In mice, targeted disruption of Rspo3 leads to embryonic lethality caused by vascular defects. Specifically in the placenta, remodeling of the vascular plexus is impaired. In human endothelial cells, R-spondin signaling promotes proliferation and sprouting angiogenesis in vitro, indicating that Rspo3 can regulate endothelial cells directly. We show that vascular endothelial growth factor is an immediate early response gene and a mediator of R-spondin signaling. The results identify Rspo3 as a novel, evolutionarily conserved angiogenic factor in embryogenesis.
Division of Molecular Embryology, German Cancer Research Center, Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany.
Olga
O
Kazanskaya
Bisei
B
Ohkawara
Melanie
M
Heroult
Wei
W
Wu
Nicole
N
Maltry
Hellmut G
HG
Augustin
Christof
C
Niehrs
D000818:Animals; D001773:Blood Cells / Q000166:cytology*; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D051379:Mice; D018919:Neovascularization, Physiologic; D010920:Placenta / Q000378:metabolism; D015398:Signal Transduction; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000098907:R-Spondins
D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; C517523:R-spondin3 protein, mouse; C534758:Rspo3 protein, Xenopus; D000098907:R-Spondins