Abstract
Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we show that the endothelial Unc5B receptor controls BBB integrity by maintaining Wnt/β-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice leads to BBB leak from brain capillaries that convert to a barrier-incompetent state with reduced Claudin-5 and increased PLVAP expression. Loss of Unc5B decreases BBB Wnt/β-catenin signaling, and β-catenin overexpression rescues Unc5B mutant BBB defects. Mechanistically, the Unc5B ligand Netrin-1 enhances Unc5B interaction with the Wnt co-receptor LRP6, induces its phosphorylation and activates Wnt/β-catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin-1 binding to Unc5B causes a transient BBB breakdown and disruption of Wnt signaling, followed by neurovascular barrier resealing. These data identify Netrin-1-Unc5B signaling as a ligand-receptor pathway that regulates BBB integrity, with implications for CNS diseases.
Highlights
Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS)
We show that intravenous delivery of monoclonal antibodies blocking Netrin-1 binding to Unc5B induce transient BBB opening to bioactive molecules, which could be useful for drug delivery in various neurological diseases
Quantification of cadaverine extravasation revealed significantly increased leak across the BBB in Unc5BiECko brains when compared to controls, while the vascular permeability to cadaverine in other Unc5BiECko organs was similar to controls (Fig. 1c), indicating that Unc5B has a CNS-selective BBB-protective function in adult mice
Summary
Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). We show that the endothelial Unc5B receptor controls BBB integrity by maintaining Wnt/β-catenin signaling. Intravenous delivery of antibodies blocking Netrin-1 binding to Unc5B causes a transient BBB breakdown and disruption of Wnt signaling, followed by neurovascular barrier resealing. These data identify Netrin-1-Unc5B signaling as a ligand-receptor pathway that regulates BBB integrity, with implications for CNS diseases. Inducible endothelial-specific Unc5B deletions in adult mice leads to reduced Wnt/β-catenin signaling and BBB leak for tracers up to 40 kDa. Unc5B and β-catenin genetically interact in ECs to maintain BBB integrity and overexpressing an activated form of β-catenin rescues BBB defects induced by loss of Unc5B. We show that intravenous delivery of monoclonal antibodies blocking Netrin-1 binding to Unc5B induce transient BBB opening to bioactive molecules, which could be useful for drug delivery in various neurological diseases
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