1. Endothelial Unc5B controls blood-brain barrier integrity
- Author
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Doyeun Kim, Jessica Furtado, Laurent Jacob, Laurence Pibouin-Fragner, Lena Claesson-Welsh, Nawal Maïssa, Dritan Agalliu, Y. Xu, Anne Eichmann, Kevin Boyé, Mathilde Poulet, Geraldo Lh, Bertrand Tavitian, Susan L. Ackerman, and Nelson B
- Subjects
Chemistry ,Mutant ,Central nervous system ,Regulator ,Wnt signaling pathway ,LRP6 ,Blood–brain barrier ,Cell biology ,medicine.anatomical_structure ,nervous system ,cardiovascular system ,medicine ,Phosphorylation ,Receptor - Abstract
Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we showed that the endothelial Netrin1 receptor Unc5B controls BBB integrity by maintaining Wnt/β–catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice led to region and size-selective BBB opening. Loss of Unc5B decreased BBB Wnt/β–catenin signaling, and β–catenin overexpression rescued Unc5B mutant BBB defects. Mechanistically, Netrin1 enhanced Unc5B interaction with the Wnt co-receptor LRP6, induced its phosphorylation and activated Wnt/β–catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin1 binding to Unc5B caused a transient disruption of Wnt signaling and BBB breakdown, followed by neurovascular barrier resealing. These data identify Netrin-Unc5B signaling as a novel regulator of BBB integrity with potential therapeutic utility for CNS diseases.
- Published
- 2021