Rspo1/Wnt signaling promotes angiogenesis via Vegfc/Vegfr3
- Authors
- Gore, A.V., Swift, M.R., Cha, Y.R., Lo, B., McKinney, M.C., Li, W., Castranova, D., Davis, A., Mukouyama, Y.S., and Weinstein, B.M.
- ID
- ZDB-PUB-111027-31
- Date
- 2011
- Source
- Development (Cambridge, England) 138(22): 4875-4886 (Journal)
- Registered Authors
- Castranova, Dan, Cha, Young, Davis, Andrew, Gore, Aniket, Lo, Brigid, Swift, Matthew Russell, Weinstein, Brant M.
- Keywords
- angiogenesis, Vegfc, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cells, Cultured
- Embryo, Nonmammalian
- Gene Expression Regulation, Developmental
- Models, Biological
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Physiologic/genetics*
- Up-Regulation/genetics
- Up-Regulation/physiology
- Vascular Endothelial Growth Factor C/genetics
- Vascular Endothelial Growth Factor C/metabolism
- Vascular Endothelial Growth Factor C/physiology*
- Vascular Endothelial Growth Factor Receptor-3/genetics
- Vascular Endothelial Growth Factor Receptor-3/metabolism
- Vascular Endothelial Growth Factor Receptor-3/physiology*
- Wnt Proteins/genetics
- Wnt Proteins/metabolism
- Wnt Signaling Pathway/genetics
- Wnt Signaling Pathway/physiology*
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/physiology
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Zebrafish Proteins/physiology*
- PubMed
- 22007135 Full text @ Development
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.