TY - JOUR TI - Nano-scale architecture of blood-brain barrier tight-junctions AU - Sasson, Esther AU - Anzi, Shira AU - Bell, Batia AU - Yakovian, Oren AU - Zorsky, Meshi AU - Deutsch, Urban AU - Engelhardt, Britta AU - Sherman, Eilon AU - Vatine, Gad AU - Dzikowski, Ron AU - Ben-Zvi, Ayal A2 - Bautch, Victoria L A2 - Akhmanova, Anna VL - 10 PY - 2021 DA - 2021/12/24 SP - e63253 C1 - eLife 2021;10:e63253 DO - 10.7554/eLife.63253 UR - https://doi.org/10.7554/eLife.63253 AB - 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. KW - blood-brain-barrier KW - tight-junction KW - super-resolution KW - endothelium JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -