LSR/angulin-1 is a tricellular tight junction protein involved in blood-brain barrier formation.
The blood-brain barrier (BBB) is a term used to describe the unique properties of central nervous system (CNS) blood vessels. One important BBB property is the formation of a paracellular barrier made by tight junctions (TJs) between CNS endothelial cells (ECs). Here, we show that Lipolysis-stimulated lipoprotein receptor (LSR), a component of paracellular junctions at points in which three cell membranes meet, is greatly enriched in CNS ECs compared with ECs in other nonneural tissues. We demonstrate that LSR is specifically expressed at tricellular junctions and that its expression correlates with the onset of BBB formation during embryogenesis. We further demonstrate that the BBB does not seal during embryogenesis in Lsr knockout mice with a leakage to small molecules. Finally, in mouse models in which BBB was disrupted, including an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and a middle cerebral artery occlusion (MCAO) model of stroke, LSR was down-regulated, linking loss of LSR and pathological BBB leakage.
Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 fsohet@ucsd.edu rdaneman@ucsd.edu.
Fabien
F
Sohet
Department of Anatomy, Department of Pediatrics, and Department of Neurology, University of California, San Francisco, San Francisco, CA 94143.
Christina
C
Lin
Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093.
Roeben N
RN
Munji
Department of Anatomy, Department of Pediatrics, and Department of Neurology, University of California, San Francisco, San Francisco, CA 94143.
Seo Yeon
SY
Lee
Department of Anatomy, Department of Pediatrics, and Department of Neurology, University of California, San Francisco, San Francisco, CA 94143.
Nadine
N
Ruderisch
Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093.
Allison
A
Soung
Department of Anatomy, Department of Pediatrics, and Department of Neurology, University of California, San Francisco, San Francisco, CA 94143.
Thomas D
TD
Arnold
Department of Anatomy, Department of Pediatrics, and Department of Neurology, University of California, San Francisco, San Francisco, CA 94143.
Nikita
N
Derugin
Department of Anatomy, Department of Pediatrics, and Department of Neurology, University of California, San Francisco, San Francisco, CA 94143.
Zinaida S
ZS
Vexler
Unité de Recherche Animal et Fonctionnalités des Produits Animaux (URAFPA), EA3998, Université de Lorraine, 54000 Nancy, France.
Frances T
FT
Yen
Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 Department of Pharmacology and Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093 fsohet@ucsd.edu rdaneman@ucsd.edu.
Richard
R
Daneman
D000818:Animals; D001812:Blood-Brain Barrier / Q000196:embryology / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018110:Receptors, Lipoprotein / Q000502:physiology*; D019108:Tight Junctions / Q000378:metabolism*
D018110:Receptors, Lipoprotein; C000592022:LSR protein, mouse