During embryogenesis, two sequential processes form the vasculature: during vasculogenesis, endothelial progenitor cells form the primary vascular bed; subsequently, during angiogenesis, additional vessels sprout and grow from pre-existing vessels. Here, Aniket Gore, Brant Weinstein and co-workers identify a novel signalling pathway that promotes developmental angiogenesis in zebrafish (see ). Their first clue to this pathway came when they identified a mutation in R-spondin1 (rspo1) during a forward-genetic screen for angiogenesis-deficient zebrafish mutants. Embryos lacking rspo1 or its receptor kremen form primary vessels, they report, but do not undergo angiogenesis. R-spondin is a Wnt signalling regulator and, by functionally manipulating different members of the Wnt pathway, the researchers show that canonical Wnt signalling is required downstream of rspo1 for sprouting angiogenesis. Finally, they show that Vegfc/Vegfr3 signalling mediates the pro-angiogenic effects of Rspo1/Wnt signalling and that all four proteins are expressed by the endothelium during sprouting angiogenesis. Together, these results suggest that Rspo1-Wnt-Vegfc-Vegfr3 signalling is an endothelial-autonomous permissive cue for developmental angiogenesis.
