The Wnt signaling regulator R-spondin 3 promotes angioblast and vascular development

Abstract

The vertebrate embryonic vasculature develops from angioblasts, which are specified from mesodermal precursors and develop in close association with blood cells. The signals that regulate embryonic vasculogenesis and angiogenesis are incompletely understood. Here, we show that R-spondin 3 (Rspo3), a member of a novel family of secreted proteins in vertebrates that activate Wnt/β-catenin signaling, plays a key role in these processes. In Xenopus embryos, morpholino antisense knockdown of Rspo3 induces vascular defects because Rspo3 is essential for regulating the balance between angioblast and blood cell specification. In mice, targeted disruption of Rspo3 leads to embryonic lethality caused by vascular defects. Specifically in the placenta, remodeling of the vascular plexus is impaired. In human endothelial cells, R-spondin signaling promotes proliferation and sprouting angiogenesis in vitro, indicating that Rspo3 can regulate endothelial cells directly. We show that vascular endothelial growth factor is an immediate early response gene and a mediator of R-spondin signaling. The results identify Rspo3 as a novel, evolutionarily conserved angiogenic factor in embryogenesis.

Wnt/β-catenin signaling is involved in the induction and maintenance of primitive hematopoiesis in the vertebrate embryo

“…R-spondin 3 (Rspo3), a secreted ligand that can also activate the Wnt/β-catenin pathway, was recently shown to be required for endothelial differentiation, actually at the expense of erythrocyte differentiation (17). Expression of Rspo3 and the endothelial marker Xfli1 was slightly reduced in Wnt4 morphant embryos (SI Appendix, Fig.…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…As in Xenopus, mouse Rspo3 is required for Wnt/ b-catenin-mediated induction of vascular endothelial growth factor (VEGF). Moreover, recombinant Rspo3 promotes proliferation and angiogenesis in endothelial cell lines (Kazanskaya et al 2008).…”

“…In Xenopus embryos, Rspo3 regulates the balance between hematopoietic and endo-thelial differentiation by promoting angioblast specification and inhibiting blood cell specification. It does so by promoting Wnt/b-catenin signaling, which is required for expression of VEGF (Kazanskaya et al 2008). In mice, targeted deletion of Rspo3 is embryonic lethal because of angiogenesis defects in placenta and yolk sac (Aoki et al 2007;Kazanskaya et al 2008).…”

“…It does so by promoting Wnt/b-catenin signaling, which is required for expression of VEGF (Kazanskaya et al 2008). In mice, targeted deletion of Rspo3 is embryonic lethal because of angiogenesis defects in placenta and yolk sac (Aoki et al 2007;Kazanskaya et al 2008). As in Xenopus, mouse Rspo3 is required for Wnt/ b-catenin-mediated induction of vascular endothelial growth factor (VEGF).…”

Differential Regulation of CXCL5 by FGF2 in Osteoblastic and Endothelial Niche Cells Supports Hematopoietic Stem Cell Migration

“…Rspo2 knockout mice exhibit limb loss and lung hypoplasia, and Rspo3 knockout mice have embryonic vascular deficiencies. Rspo3 signaling is required to support endothelial cell growth and remodeling [50,51]. Thus, combined with our microarray data, it is feasible that FGF2 induction and the increased niche function of endothelial cells by FGF2 induction might also, in part, be due to the supportive role of Rspo3 and 2 in cell growth and remodeling.…”