Nano-scale architecture of blood-brain barrier tight-junctions
- Hebrew University of Jerusalem, Israel
- Ben-Gurion University of the Negev, Israel
- 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
Article and author information
Author details
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
© 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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Nano-scale architecture of blood-brain barrier tight-junctions
eLife 10:e63253.
https://doi.org/10.7554/eLife.63253
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