Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Antigens, CD / genetics*
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Antigens, CD / metabolism
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Blood-Brain Barrier / growth & development
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Blood-Brain Barrier / metabolism
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Brain / blood supply
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Brain / growth & development
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Brain / metabolism*
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Cadherins / genetics*
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Cadherins / metabolism
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Capillaries / growth & development
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Capillaries / metabolism
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism
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Cerebrovascular Circulation / genetics
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Embryo, Nonmammalian
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Gene Expression Regulation, Developmental
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Genes, Reporter
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Neovascularization, Physiologic / genetics*
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Receptors, Lysosphingolipid / genetics*
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Receptors, Lysosphingolipid / metabolism
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Red Fluorescent Protein
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Wnt Signaling Pathway*
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Zebrafish / genetics*
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Zebrafish / growth & development
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Zebrafish / metabolism
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Zebrafish Proteins / genetics*
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Zebrafish Proteins / metabolism
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beta Catenin / genetics*
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beta Catenin / metabolism
Substances
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Antigens, CD
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Cadherins
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Cell Adhesion Molecules
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Luminescent Proteins
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Receptors, Lysosphingolipid
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Zebrafish Proteins
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beta Catenin
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cadherin 5
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ctnnb1 protein, zebrafish