Article Dans Une Revue Nature Communications Année : 2022

Endothelial Unc5B controls blood-brain barrier integrity

Jessica Furtado
  • Fonction : Auteur
Dritan Agalliu
Lena Claesson-Welsh
Susan L Ackerman
  • Fonction : Auteur

Résumé

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/βcatenin signaling, and β-catenin overexpression rescues Unc5B mutant BBB defects. Mechanistically, the Unc5B ligand Netrin-1 enhances Unc5B interaction with the Wnt coreceptor 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.

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hal-05136820 , version 1 (30-06-2025)

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Kevin Boyé, Luiz Henrique Geraldo, Jessica Furtado, Laurence Pibouin-Fragner, Mathilde Poulet, et al.. Endothelial Unc5B controls blood-brain barrier integrity. Nature Communications, 2022, 13, ⟨10.1038/s41467-022-28785-9⟩. ⟨hal-05136820⟩
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