TY  - JOUR
AU  - Scholz, Beate
AU  - Korn, Claudia
AU  - Wojtarowicz, Jessica
AU  - Mogler, Carolin
AU  - Augustin, Iris
AU  - Boutros, Michael
AU  - Niehrs, Christof
AU  - Augustin, Hellmut
TI  - Endothelial RSPO3 Controls Vascular Stability and Pruning through Non-canonical WNT/Ca(2+)/NFAT Signaling.
JO  - Developmental cell
VL  - 36
IS  - 1
SN  - 1534-5807
CY  - Cambridge, Mass.
PB  - Cell Press
M1  - DKFZ-2017-05597
SP  - 79 - 93
PY  - 2016
AB  - 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.
KW  - NFATC Transcription Factors (NLM Chemicals)
KW  - R-spondin3 protein, mouse (NLM Chemicals)
KW  - Thrombospondins (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - Wnt Proteins (NLM Chemicals)
KW  - Calcium (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26766444
DO  - DOI:10.1016/j.devcel.2015.12.015
UR  - https://inrepo02.dkfz.de/record/130518
ER  -