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Development. 2011 Nov;138(22):4875-86. doi: 10.1242/dev.068460. Epub 2011 Oct 17.

Rspo1/Wnt signaling promotes angiogenesis via Vegfc/Vegfr3.

Author information

1
Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, 6B/3B309, Bethesda, MD 20892, USA.

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.

PMID:
22007135
PMCID:
PMC3201658
DOI:
10.1242/dev.068460
[Indexed for MEDLINE]
Free PMC Article
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