Abstract
Here, we show that a novel Rspo1-Wnt-Vegfc-Vegfr3 signaling pathway plays an essential role in developmental angiogenesis. A mutation in R-spondin1 (rspo1), a Wnt signaling regulator, was uncovered during a forward-genetic screen for angiogenesis-deficient mutants in the zebrafish. Embryos lacking rspo1 or the proposed rspo1 receptor kremen form primary vessels by vasculogenesis, but are defective in subsequent angiogenesis. Endothelial cell-autonomous inhibition of canonical Wnt signaling also blocks angiogenesis in vivo. The pro-angiogenic effects of Rspo1/Wnt signaling are mediated by Vegfc/Vegfr3(Flt4) signaling. Vegfc expression is dependent on Rspo1 and Wnt, and Vegfc and Vegfr3 are necessary to promote angiogenesis downstream from Rspo1-Wnt. As all of these molecules are expressed by the endothelium during sprouting stages, these results suggest that Rspo1-Wnt-VegfC-Vegfr3 signaling plays a crucial role as an endothelial-autonomous permissive cue for developmental angiogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Cells, Cultured
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Embryo, Nonmammalian
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Gene Expression Regulation, Developmental
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Models, Biological
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Neovascularization, Physiologic / genetics*
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Thrombospondins
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Up-Regulation / genetics
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Up-Regulation / physiology
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Vascular Endothelial Growth Factor C / genetics
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Vascular Endothelial Growth Factor C / metabolism
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Vascular Endothelial Growth Factor C / physiology*
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Vascular Endothelial Growth Factor Receptor-3 / genetics
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Vascular Endothelial Growth Factor Receptor-3 / metabolism
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Vascular Endothelial Growth Factor Receptor-3 / physiology*
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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Wnt Signaling Pathway / genetics
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Wnt Signaling Pathway / physiology*
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Zebrafish / embryology
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Zebrafish / genetics
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Zebrafish / physiology
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism
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Zebrafish Proteins / physiology*
Substances
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RSPO1 protein, zebrafish
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Thrombospondins
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Vascular Endothelial Growth Factor C
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Wnt Proteins
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Zebrafish Proteins
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vascular endothelial growth factor C, zebrafish
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Vascular Endothelial Growth Factor Receptor-3