Wnt/β-catenin signaling controls development of the blood-brain barrier

• Published in: The Journal of cell biology Vol. 183; no. 3; pp. 409 - 417
• Main Authors: Liebner, Stefan, Corada, Monica, Bangsow, Thorsten, Babbage, Jane, Taddei, Andrea, Czupalla, Cathrin J, Reis, Marco, Felici, Angelina, Wolburg, Hartwig, Fruttiger, Marcus, Taketo, Makoto M, von Melchner, Harald, Plate, Karl Heinz, Gerhardt, Holger, Dejana, Elisabetta
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 03.11.2008; Rockefeller University Press
• Subjects: Animals; Antibodies; beta Catenin - physiology; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Blood brain barrier; Blood-Brain Barrier - physiology; Brain; Cell lines; Central Nervous System - physiology; Cerebrovascular Circulation - physiology; Endothelial cells; Genes, Reporter; Humans; Mice; Models, Animal; Neovascularization, Physiologic - physiology; Research universities; Reverse transcriptase polymerase chain reaction; RNA; Signal Transduction; Tight junctions; Up regulation; Wnt Proteins - physiology
• ISSN: 0021-9525; 1540-8140; 1540-8140
• DOI: 10.1083/jcb.200806024

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.