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Endothelial Unc5B controls blood-brain barrier integrity

Author

Listed:
  • Kevin Boyé

    (Yale University School of Medicine)

  • Luiz Henrique Geraldo

    (Yale University School of Medicine
    Université de Paris, INSERM, PARCC)

  • Jessica Furtado

    (Yale University School of Medicine)

  • Laurence Pibouin-Fragner

    (Université de Paris, INSERM, PARCC)

  • Mathilde Poulet

    (Yale University School of Medicine
    Université de Paris, INSERM, PARCC)

  • Doyeun Kim

    (OliX pharmaceuticals)

  • Bryce Nelson

    (Yale University School of Medicine)

  • Yunling Xu

    (Université de Paris, INSERM, PARCC)

  • Laurent Jacob

    (Université de Paris, INSERM, PARCC)

  • Nawal Maissa

    (Université de Paris, INSERM, PARCC)

  • Dritan Agalliu

    (Columbia University Irving Medical Center)

  • Lena Claesson-Welsh

    (Uppsala University)

  • Susan L. Ackerman

    (University of California San Diego and Howard Hughes Medical Institute)

  • Anne Eichmann

    (Yale University School of Medicine
    Université de Paris, INSERM, PARCC
    Yale University School of Medicine)

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.

Suggested Citation

  • Kevin Boyé & Luiz Henrique Geraldo & Jessica Furtado & Laurence Pibouin-Fragner & Mathilde Poulet & Doyeun Kim & Bryce Nelson & Yunling Xu & Laurent Jacob & Nawal Maissa & Dritan Agalliu & Lena Claess, 2022. "Endothelial Unc5B controls blood-brain barrier integrity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28785-9
    DOI: 10.1038/s41467-022-28785-9
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    References listed on IDEAS

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