Wnt/beta-catenin signaling controls development of the blood-brain barrier |
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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 |
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Institution: | Institute of Neurology (Edinger Institute), Johann Wolfgang Goethe University, 60325 Frankfurt, Germany. elisabetta.dejana@ifom-ieo-campus.it |
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Abstract: | 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. |
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