title: Rspo1/Wnt signaling promotes angiogenesis via Vegfc/Vegfr3.
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.
authors: Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, 6B/3B309, Bethesda, MD 20892, USA.
authors: Aniket V
authors: AV
authors: Gore
authors: Matthew R
authors: MR
authors: Swift
authors: Young R
authors: YR
authors: Cha
authors: Brigid
authors: B
authors: Lo
authors: Mary C
authors: MC
authors: McKinney
authors: Wenling
authors: W
authors: Li
authors: Daniel
authors: D
authors: Castranova
authors: Andrew
authors: A
authors: Davis
authors: Yoh-suke
authors: YS
authors: Mukouyama
authors: Brant M
authors: BM
authors: Weinstein
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics*; D019699:Thrombospondins; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C556668:RSPO1 protein, zebrafish; D019699:Thrombospondins; D042582:Vascular Endothelial Growth Factor C; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C493178:vascular endothelial growth factor C, zebrafish; D040321:Vascular Endothelial Growth Factor Receptor-3