Wnt/β-catenin signaling regulates VE-cadherin-mediated anastomosis of brain capillaries by counteracting S1pr1 signaling

• Published in: Nature communications Vol. 9; no. 1; pp. 4860 - 17
• Main Authors: Hübner, Kathleen, Cabochette, Pauline, Diéguez-Hurtado, Rodrigo, Wiesner, Cora, Wakayama, Yuki, Grassme, Kathrin S., Hubert, Marvin, Guenther, Stefan, Belting, Heinz-Georg, Affolter, Markus, Adams, Ralf H., Vanhollebeke, Benoit, Herzog, Wiebke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.11.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 14/19; 38; 38/91; 42/70; 631/136/16; 631/136/334/1874/763; 631/378/1341; 64/116; 96; Anastomosis; Angiogenesis; Animals; Animals, Genetically Modified; Antigens, CD - genetics; Antigens, CD - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Blood-brain barrier; Blood-Brain Barrier - growth & development; Blood-Brain Barrier - metabolism; Brain - blood supply; Brain - growth & development; Brain - metabolism; Cadherins; Cadherins - genetics; Cadherins - metabolism; Capillaries; Capillaries - growth & development; Capillaries - metabolism; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell junctions; Central nervous system; Cerebrovascular Circulation - genetics; Embryo, Nonmammalian; Embryos; Gene Expression Regulation, Developmental; Genes, Reporter; Humanities and Social Sciences; Image resolution; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; multidisciplinary; Neovascularization, Physiologic - genetics; Neurodegenerative diseases; Neuroimaging; Neurological diseases; Receptors, Lysosphingolipid - genetics; Receptors, Lysosphingolipid - metabolism; Red Fluorescent Protein; Science; Science (multidisciplinary); Signaling; Sphingosine 1-phosphate; Vascularization; Wnt protein; Wnt Signaling Pathway; Zebrafish - genetics; Zebrafish - growth & development; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07302-x

Canonical Wnt signaling is crucial for vascularization of the central nervous system and blood-brain barrier (BBB) formation. BBB formation and modulation are not only important for development, but also relevant for vascular and neurodegenerative diseases. However, there is little understanding of how Wnt signaling contributes to brain angiogenesis and BBB formation. Here we show, using high resolution in vivo imaging and temporal and spatial manipulation of Wnt signaling, different requirements for Wnt signaling during brain angiogenesis and BBB formation. In the absence of Wnt signaling, premature Sphingosine-1-phosphate receptor (S1pr) signaling reduces VE-cadherin and Esama at cell-cell junctions. We suggest that Wnt signaling suppresses S1pr signaling during angiogenesis to enable the dynamic junction formation during anastomosis, whereas later S1pr signaling regulates BBB maturation and VE-cadherin stabilization. Our data provides a link between brain angiogenesis and BBB formation and identifies Wnt signaling as coordinator of the timing and as regulator of anastomosis. Wnt signaling is known to regulate the formation of the blood-brain barrier. Here Hübner et al. dissect the underlying mechanisms using high resolution live imaging in zebrafish, and find that Wnt regulates anastomosis of angiogenic sprouts in the brain by counteracting sphingosine-1-phosphate receptor signaling.