Nano-scale architecture of blood-brain barrier tight-junctions

  1. Esther Sasson
  2. Shira Anzi
  3. Batia Bell
  4. Oren Yakovian Mr.
  5. Meshi Zorsky
  6. Urban Deutsch
  7. Britta Engelhardt
  8. Eilon Sherman
  9. Gad Vatine
  10. Ron Dzikowski
  11. Ayal Ben-Zvi  Is a corresponding author
  1. Hebrew University of Jerusalem, Israel
  2. Ben-Gurion University of the Negev, Israel
  3. University of Bern, Switzerland

Abstract

Tight junctions (TJs) between blood-brain barrier (BBB) endothelial cells construct a robust physical barrier, whose damage underlies BBB dysfunctions related to several neurodegenerative diseases. What makes these highly specialized BBB-TJs extremely restrictive remains unknown. Here, we use super-resolution microscopy (dSTORM) to uncover new structural and functional properties of BBB TJs. Focusing on three major components, Nano-scale resolution revealed sparse (occludin) vs. clustered (ZO1/claudin-5) molecular architecture. In mouse development, permeable TJs become first restrictive to large molecules, and only later to small molecules, with claudin-5 proteins arrangement compacting during this maturation process. Mechanistically, we reveal that ZO1 clustering is independent of claudin-5 in-vivo. In contrast to accepted knowledge, we found that in the developmental context, total levels of claudin-5 inversely correlate with TJ functionality. Our super-resolution studies provide a unique perspective of BBB TJs and open new directions for understanding TJ functionality in biological barriers, ultimately enabling restoration in disease or modulation for drug delivery.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Tiff and ND2 images and CSV files for STORM imaging are available in deposited archive at EBI (BioStudies accession number S-BSST744). Any additional images of interest or different image formats could be provided upon request to the corresponding author

The following data sets were generated

Article and author information

Author details

  1. Esther Sasson

    Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Shira Anzi

    Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Batia Bell

    Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Oren Yakovian Mr.

    Racah Institute of Physics, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Meshi Zorsky

    Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Urban Deutsch

    Theodor Kocher Institute, University of Bern, Bern, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  7. Britta Engelhardt

    Theodor Kocher Institute, University of Bern, Bern, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  8. Eilon Sherman

    Racah Institute of Physics, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Gad Vatine

    Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Ron Dzikowski

    Department of Microbiology and Molecular Genetics, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  11. Ayal Ben-Zvi

    Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel
    For correspondence
    ayalb@ekmd.huji.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4012-7789

Funding

Israel Science Foundation (1882/16)

  • Ayal Ben-Zvi

Israel Science Foundation (2402/16)

  • Ayal Ben-Zvi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animals were treated according to institutional guidelines approved by the Institutional Animal Care and Use Committee (IACUC) at Hebrew University (Protocol #MD-15-14449-4).

Reviewing Editor

  1. Victoria L Bautch, University of North Carolina, Chapel Hill, United States

Publication history

  1. Received: September 18, 2020
  2. Preprint posted: August 13, 2021 (view preprint)
  3. Accepted: October 1, 2021
  4. Accepted Manuscript published: December 24, 2021 (version 1)
  5. Version of Record published: January 10, 2022 (version 2)

Copyright

© 2021, Sasson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Esther Sasson
  2. Shira Anzi
  3. Batia Bell
  4. Oren Yakovian Mr.
  5. Meshi Zorsky
  6. Urban Deutsch
  7. Britta Engelhardt
  8. Eilon Sherman
  9. Gad Vatine
  10. Ron Dzikowski
  11. Ayal Ben-Zvi
(2021)
Nano-scale architecture of blood-brain barrier tight-junctions
eLife 10:e63253.
https://doi.org/10.7554/eLife.63253

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