The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells

Author:

Artus Cédric123,Glacial Fabienne123,Ganeshamoorthy Kayathiri123,Ziegler Nicole4,Godet Maeva123,Guilbert Thomas1,Liebner Stefan4,Couraud Pierre-Olivier123

Affiliation:

1. INSERM U1016, Institut Cochin, Paris, France

2. CNRS, UMR 8104, Paris, France

3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

4. Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt Medical School, Frankfurt, Germany

Abstract

Wnt morphogens released by neural precursor cells were recently reported to control blood–brain barrier (BBB) formation during development. Indeed, in mouse brain endothelial cells, activation of the Wnt/ β-catenin signaling pathway, also known as the canonical Wnt pathway, was shown to stabilize endothelial tight junctions (TJs) through transcriptional regulation of the expression of TJ proteins. Because Wnt proteins activate several distinct β-catenin-dependent and independent signaling pathways, this study was designed to assess whether the noncanonical Wnt/Par/aPKC planar cell polarity (PCP) pathway might also control TJ integrity in brain endothelial cells. First we established, in the hCMEC/D3 human brain endothelial cell line, that the Par/aPKC PCP complex colocalizes with TJs and controls apicobasal polarization. Second, using an siRNA approach, we showed that the Par/aPKC PCP complex regulates TJ stability and reassembling after osmotic shock. Finally, we provided evidence that Wnt5a signals in hCMEC/D3 cells through activation of the Par/aPKC PCP complex, independently of the Wnt canonical β-catenin-dependent pathway and significantly contributes to TJ integrity and endothelial apicobasal polarity. In conclusion, this study suggests that the Wnt/Par/aPKC PCP pathway, in addition to the Wnt/ β-catenin canonical pathway, is a key regulator of the BBB.

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Neurology (clinical),Neurology

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