The Wnt/beta-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling.
The Wnt/beta-catenin pathway is evolutionary conserved signaling system that regulates cell differentiation and organogenesis. We show that endothelial specific stabilization of Wnt/beta-catenin signaling alters early vascular development in the embryo. The phenotype resembles that induced by upregulation of Notch signaling, including lack of vascular remodeling, altered elongation of the intersomitic vessels, defects in branching, and loss of venous identity. Both in vivo and in vitro data show that beta-catenin upregulates Dll4 transcription and strongly increases Notch signaling in the endothelium, leading to functional and morphological alterations. The functional consequences of beta-catenin signaling depend on the stage of vascular development and are lost when a gain-of-function mutation is induced at a late stage of development or postnatally. Our findings establish a link between Wnt and Notch signaling in vascular development. We propose that early and sustained beta-catenin signaling prevents correct endothelial cell differentiation, altering vascular remodeling and arteriovenous specification.
Corada
Monica
M
IFOM, The FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy.
Nyqvist
Daniel
D
Orsenigo
Fabrizio
F
Caprini
Andrea
A
Giampietro
Costanza
C
Taketo
Makoto M
MM
Iruela-Arispe
M Luisa
ML
Adams
Ralf H
RH
Dejana
Elisabetta
E
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001158:Arteries / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D014680:Veins / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C495267:CTNNB1 protein, mouse; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin