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

eLife

Shira Anzi¹  Esther Sasson¹  Ayal Ben-Zvi¹  Batia Bell¹  Ron Dzikowski²  Gad Vatine³  Meshi Zorsky³  Eilon Sherman⁴  Oren Yakovian⁴  Urban Deutsch⁵  Britta Engelhardt⁵ 

[1] Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel;Department of Microbiology and Molecular Genetics, Hebrew University of Jerusalem, Jerusalem, Israel;Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel;Racah Institute of Physics, Hebrew University of Jerusalem, Jerusalem, Israel;Theodor Kocher Institute, University of Bern, Bern, Switzerland;

关键词: blood-brain-barrier;    tight-junction;    super-resolution;    endothelium;    Mouse;   

DOI  :  10.7554/eLife.63253

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY