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Published online October 27, 2008
doi:10.1083/jcb.200806024
The Journal of Cell Biology, Vol. 183, No. 3, 409-417
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Liebner et al.
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Wnt/β-catenin signaling controls development of the blood–brain barrier



Stefan Liebner1, Monica Corada3, Thorsten Bangsow2, Jane Babbage4, Andrea Taddei3, Cathrin J. Czupalla1, Marco Reis1, Angelina Felici3, Hartwig Wolburg5, Marcus Fruttiger6, Makoto M. Taketo7, Harald von Melchner2, Karl Heinz Plate1, Holger Gerhardt4, and Elisabetta Dejana3,8

1 Institute of Neurology (Edinger Institute) and 2 Institute of Molecular Hematology, Johann Wolfgang Goethe University, 60325 Frankfurt, Germany
3 Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy
4 Vascular Biology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3PX, England, UK
5 Institute of Pathology, Eberhard Karls University, 72076 Tübingen, Germany
6 Institute of Ophthalmology, University College London, London WC1E 6BT, England, UK
7 Department of Pharmacology, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto 606-8501, Japan
8 Department of Biomolecular Sciences and Biotechnologies, School of Sciences, University of Milan, 20126 Milan, Italy

Correspondence to S. Liebner: stefan.liebner{at}kgu.de; H. Gerhardt: holger.gerhardt{at}cancer.org.uk; or E. Dejana: elisabetta.dejana{at}ifom-ieo-campus.it

The blood–brain barrier (BBB) is confined to the endothelium of brain capillaries and is indispensable for fluid homeostasis and neuronal function. In this study, we show that endothelial Wnt/β-catenin (β-cat) signaling regulates induction and maintenance of BBB characteristics during embryonic and postnatal development. Endothelial specific stabilization of β-cat in vivo enhances barrier maturation, whereas inactivation of β-cat causes significant down-regulation of claudin3 (Cldn3), up-regulation of plamalemma vesicle-associated protein, and BBB breakdown. Stabilization of β-cat in primary brain endothelial cells (ECs) in vitro by N-terminal truncation or Wnt3a treatment increases Cldn3 expression, BBB-type tight junction formation, and a BBB characteristic gene signature. Loss of β-cat or inhibition of its signaling abrogates this effect. Furthermore, stabilization of β-cat also increased Cldn3 and barrier properties in nonbrain-derived ECs. These findings may open new therapeutic avenues to modulate endothelial barrier function and to limit the devastating effects of BBB breakdown.

Abbreviations used in this paper: 4OHT, 4-hydroxy-tamoxifen; BAT-Gal, β-cat–activated transgene driving expression of nuclear β-galactosidase reporter; BBB, blood–brain barrier; β-cat, β-catenin; Cldn, claudin; CM, conditioned medium; EC, endothelial cell; GOF, gain of function; IF, immunofluorescence; IHC, immunohistochemistry; Lef, lymphoid enhancer factor; LOF, loss of function; MBE, mouse brain microvascular EC; Ocln, occludin; P-face, protoplasmic fracture face; Plako, plakoglobin; Plvap, plamalemma vesicle-associated protein; TAT, transactivating regulatory protein; TCF, T cell factor; TJ, tight junction; VE-cad, vascular endothelial cadherin; ZO-1, zonula occludens 1.

© 2008 Liebner et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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