LSR/angulin-1 is a tricellular tight junction protein involved in blood–brain barrier formation
Open accessAbstract
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.
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Lsr-/- embryos lacking lipolysis-stimulated lipoprotein receptor (LSR), a component of tricellular junctions, exhibit a BBB open to molecules that are ~10 kDa.
“whereas Lsr -/ -embryos lacking lipolysis-stimulated lipoprotein receptor (LSR), a component of tricellular junctions, exhibit a BBB open to molecules that are ~10 kDa (551).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [551]
The Results and discussion section reports that the BBB of Lsr−/− embryos remains permeable to the small Sulfo-NHS-biotin tracer at E14.5. But its 10-kDa dextran experiment found minimal leakage in all genotypes at E12.5, rather than an Lsr−/− BBB open to molecules of that size. The copy does not report a 10-kDa permeability test at E14.5. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredLSR/angulin-1 has been previously identified at peripheral tricellular junctions.
“BBB also expresses the TJ protein LSR, also known as angulin-1, that has been previously identified at peripheral tricellular junctions (551).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [551]
The blood-brain barrier expresses the tight junction protein LSR, also known as angulin-1.
“BBB also expresses the TJ protein LSR, also known as angulin-1, that has been previously identified at peripheral tricellular junctions (551).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [551]
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References 25 · Cited by 139
Research works printed but not linked: 24
- Ben-Zvi A., Lacoste B., Kur E., Andreone B.J., Mayshar Y., Yan H., and Gu C. 2014 Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature. 509: 507– 511 10.1038/nature13324 24828040 PMC4134871 · DOI · Paper page
- Daneman R. 2012 The blood-brain barrier in health and disease. Ann. Neurol. 72: 648– 672 10.1002/ana.23648 23280789 · DOI
- Daneman R., Zhou L., Agalliu D., Cahoy J.D., Kaushal A., and Barres B.A. 2010a The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS ONE. 5: e13741 10.1371/journal.pone.0013741 21060791 PMC2966423 · DOI · Paper page
- Daneman R., Zhou L., Kebede A.A., and Barres B.A. 2010b Nature. 468: 562– 566 10.1038/nature09513 20944625 PMC3241506 · DOI · Paper page
- Dietschy J.M., and Turley S.D. 2001 Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 12: 105– 112 10.1097/00041433-200104000-00003 11264981 · DOI · Paper page
- Dietschy J.M., and Turley S.D. 2004 Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J. Lipid Res. 45: 1375– 1397 10.1194/jlr.R400004-JLR200 15254070 · DOI · Paper page
- Günzel D., and Yu A.S. 2013 Claudins and the modulation of tight junction permeability. Physiol. Rev. 93: 525– 569 10.1152/physrev.00019.2012 23589827 PMC3768107 · DOI · Paper page
- Higashi T., Tokuda S., Kitajiri S., Masuda S., Nakamura H., Oda Y., and Furuse M. 2013 Analysis of the ‘angulin’ proteins LSR, ILDR1 and ILDR2—tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis. J. Cell Sci. 126: 966– 977 10.1242/jcs.116442 23239027 · DOI
- Hirase T., Staddon J.M., Saitou M., Ando-Akatsuka Y., Itoh M., Furuse M., Fujimoto K., Tsukita S., and Rubin L.L. 1997 Occludin as a possible determinant of tight junction permeability in endothelial cells. J. Cell Sci. 110: 1603– 1613. 9247194
- Ikenouchi J., Furuse M., Furuse K., Sasaki H., Tsukita S., and Tsukita S. 2005 Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J. Cell Biol. 171: 939– 945 10.1083/jcb.200510043 16365161 PMC2171318 · DOI
- Iwamoto N., Higashi T., and Furuse M. 2014 Localization of angulin-1/LSR and tricellulin at tricellular contacts of brain and retinal endothelial cells in vivo. Cell Struct. Funct. 39: 1– 8 10.1247/csf.13015 24212375 · DOI
- Kokubo Y., Matson G.B., Derugin N., Hill T., Mancuso A., Chan P.H., and Weinstein P.R. 2002 Transgenic mice expressing human copper-zinc superoxide dismutase exhibit attenuated apparent diffusion coefficient reduction during reperfusion following focal cerebral ischemia. Brain Res. 947: 1– 8 10.1016/S0006-8993(02)02899-8 12144846 · DOI
- Liebner S., Corada M., Bangsow T., Babbage J., Taddei A., Czupalla C.J., Reis M., Felici A., Wolburg H., Fruttiger M., 2008 Wnt/β-catenin signaling controls development of the blood-brain barrier. J. Cell Biol. 183: 409– 417 10.1083/jcb.200806024 18955553 PMC2575783 · DOI · Paper page
- Masuda S., Oda Y., Sasaki H., Ikenouchi J., Higashi T., Akashi M., Nishi E., and Furuse M. 2011 LSR defines cell corners for tricellular tight junction formation in epithelial cells. J. Cell Sci. 124: 548– 555 10.1242/jcs.072058 21245199 · DOI
- Mesli S., Javorschi S., Bérard A.M., Landry M., Priddle H., Kivlichan D., Smith A.J., Yen F.T., Bihain B.E., and Darmon M. 2004 Distribution of the lipolysis stimulated receptor in adult and embryonic murine tissues and lethality of LSR-/- embryos at 12.5 to 14.5 days of gestation. Eur. J. Biochem. 271: 3103– 3114 10.1111/j.1432-1033.2004.04223.x 15265030 · DOI
- Morita K., Sasaki H., Furuse M., and Tsukita S. 1999 Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J. Cell Biol. 147: 185– 194 10.1083/jcb.147.1.185 10508865 PMC2164984 · DOI
- Saitou M., Furuse M., Sasaki H., Schulzke J.D., Fromm M., Takano H., Noda T., and Tsukita S. 2000 Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell. 11: 4131– 4142 10.1091/mbc.11.12.4131 11102513 PMC15062 · DOI · Paper page
- Siegenthaler J.A., Sohet F., and Daneman R. 2013 ‘Sealing off the CNS’: cellular and molecular regulation of blood-brain barriergenesis. Curr. Opin. Neurobiol. 23: 1057– 1064 10.1016/j.conb.2013.06.006 23867075 PMC4061913 · DOI · Paper page
- Sohet F., and Daneman R. 2013 Genetic mouse models to study blood-brain barrier development and function. Fluids Barriers CNS. 10: 3 10.1186/2045-8118-10-3 23305182 PMC3675378 · DOI
- Stenger C., Corbier C., and Yen F.T. 2012a Structure and Function of the Lipolysis Stimulated Lipoprotein Receptor. Chemical Biology. Ekinci D., editor InTech, Rijeka, Croatia 267– 292 10.5772/34657 · DOI
- Stenger C., Pinçon A., Hanse M., Royer L., Comte A., Koziel V., Olivier J.L., Pillot T., and Yen F.T. 2012b Brain region-specific immunolocalization of the lipolysis-stimulated lipoprotein receptor (LSR) and altered cholesterol distribution in aged LSR+/- mice. J. Neurochem. 123: 467– 476 10.1111/j.1471-4159.2012.07922.x 22909011 · DOI
- Thumburu K.K., Taneja S., Vasishta R.K., and Dhiman R.K. 2012 Neuropathology of acute liver failure. Neurochem. Int. 60: 672– 675 10.1016/j.neuint.2011.10.013 22198438 · DOI
- Yen F.T., Masson M., Clossais-Besnard N., André P., Grosset J.M., Bougueleret L., Dumas J.B., Guerassimenko O., and Bihain B.E. 1999 Molecular cloning of a lipolysis-stimulated remnant receptor expressed in the liver. J. Biol. Chem. 274: 13390– 13398 10.1074/jbc.274.19.13390 10224102 · DOI
- Yen F.T., Roitel O., Bonnard L., Notet V., Pratte D., Stenger C., Magueur E., and Bihain B.E. 2008 Lipolysis stimulated lipoprotein receptor: a novel molecular link between hyperlipidemia, weight gain, and atherosclerosis in mice. J. Biol. Chem. 283: 25650– 25659 10.1074/jbc.M801027200 18644789 · DOI
- Authors
- Sohet, F., Lin, C., Munji, R. N., Lee, S. Y., Ruderisch, N., Soung, A., Arnold, T. D., Derugin, N., Vexler, Z. S., Yen, F. T., & Daneman, R.
- Affiliations
- University of California San Diego (US)
- University of California, San Francisco (US)
- Laboratoire Animal et Agroécosystèmes (FR)
- Corresponding author
- Sohet, Fabien
- Daneman, Richard
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2015-03-09
- Volume
- 208
- Issue
- 6
- Pages
- 703-711
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC4362448
- OpenAlex
- W2034887716
- Cited by
- 139
- References
- 25
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 9 · 2023: 9 · 2022: 17 · 2021: 18 · 2020: 16 · 2019: 13 · 2018: 13 · 2017: 10 · 2016: 7 · 2015: 5
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS044025, R01NS076726, R01NS083688)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- lipolysis-stimulated lipoprotein receptor, tricellular tight junctions, blood-brain barrier, paracellular barrier, BBB leakage, experimental autoimmune encephalomyelitis, multiple sclerosis, middle cerebral artery occlusion, stroke, tight junction proteins
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Cell Line, Encephalomyelitis, Autoimmune, Experimental, Female, Mice, Inbred C57BL, Receptors, Lipoprotein, Mice, Knockout, Tight Junctions, Infarction, Middle Cerebral Artery
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