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

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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

1. Ayal Ben zvi
2. Esther Sasson
(2021) Nano-scale Architecture of Blood-Brain Barrier Tight-Junctions
BioStudies, S-BSST744.

https://www.ebi.ac.uk/biostudies/studies/S-BSST744?query=S-BSST744

Article and author information

Author details

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.
Shira Anzi

Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel

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The authors declare that no competing interests exist.
Batia Bell

Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel

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The authors declare that no competing interests exist.
Oren Yakovian Mr.

Racah Institute of Physics, Hebrew University of Jerusalem, Jerusalem, Israel

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The authors declare that no competing interests exist.
Meshi Zorsky

Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel

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The authors declare that no competing interests exist.
Urban Deutsch

Theodor Kocher Institute, University of Bern, Bern, Switzerland

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The authors declare that no competing interests exist.
Britta Engelhardt

Theodor Kocher Institute, University of Bern, Bern, Switzerland

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The authors declare that no competing interests exist.
Eilon Sherman

Racah Institute of Physics, Hebrew University of Jerusalem, Jerusalem, Israel

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The authors declare that no competing interests exist.
Gad Vatine

Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel

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The authors declare that no competing interests exist.
Ron Dzikowski

Department of Microbiology and Molecular Genetics, Hebrew University of Jerusalem, Jerusalem, Israel

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The authors declare that no competing interests exist.
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.

"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).

Copyright

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.