%0 Journal Article
%A Scholz, Beate
%A Korn, Claudia
%A Wojtarowicz, Jessica
%A Mogler, Carolin
%A Augustin, Iris
%A Boutros, Michael
%A Niehrs, Christof
%A Augustin, Hellmut
%T Endothelial RSPO3 Controls Vascular Stability and Pruning through Non-canonical WNT/Ca(2+)/NFAT Signaling.
%J Developmental cell
%V 36
%N 1
%@ 1534-5807
%C Cambridge, Mass.
%I Cell Press
%M DKFZ-2017-05597
%P 79 - 93
%D 2016
%X The WNT signaling enhancer R-spondin3 (RSPO3) is prominently expressed in the vasculature. Correspondingly, embryonic lethality of Rspo3-deficient mice is caused by vessel remodeling defects. Yet the mechanisms underlying vascular RSPO3 function remain elusive. Inducible endothelial Rspo3 deletion (Rspo3-iECKO) resulted in perturbed developmental and tumor vascular remodeling. Endothelial cell apoptosis and vascular pruning led to reduced microvessel density in Rspo3-iECKO mice. Rspo3-iECKO mice strikingly phenocopied the non-canonical WNT signaling-induced vascular defects of mice deleted for the WNT secretion factor Evi/Wls. An endothelial screen for RSPO3 and EVI/WLS co-regulated genes identified Rnf213, Usp18, and Trim30α. RNF213 targets filamin A and NFAT1 for proteasomal degradation attenuating non-canonical WNT/Ca(2+) signaling. Likewise, USP18 and TRIM5α inhibited NFAT1 activation. Consequently, NFAT protein levels were decreased in endothelial cells of Rspo3-iECKO mice and pharmacological NFAT inhibition phenocopied Rspo3-iECKO mice. The data identify endothelial RSPO3-driven non-canonical WNT/Ca(2+)/NFAT signaling as a critical maintenance pathway of the remodeling vasculature.
%K NFATC Transcription Factors (NLM Chemicals)
%K R-spondin3 protein, mouse (NLM Chemicals)
%K Thrombospondins (NLM Chemicals)
%K Transcription Factors (NLM Chemicals)
%K Wnt Proteins (NLM Chemicals)
%K Calcium (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:26766444
%R 10.1016/j.devcel.2015.12.015
%U https://inrepo02.dkfz.de/record/130518