Engulfed cadherin fingers are polarized junctional structures between collectively migrating endothelial cells

Abstract

The development and maintenance of tissues requires collective cell movement, during which neighboring cells coordinate the polarity of their migration machineries. Here, we ask how polarity signals are transmitted from one cell to another across symmetrical cadherin junctions, during collective migration. We demonstrate that collectively migrating endothelial cells have polarized VE-cadherin-rich membrane protrusions, “cadherin fingers”, which leading cells extend from their rear and follower cells engulf at their front, thereby generating opposite membrane curvatures and asymmetric recruitment of curvature sensing proteins. In follower cells, engulfment of cadherin fingers occurs along with the formation of a lamellipodia-like zone with low actomyosin contractility, and requires VE-cadherin/catenin complexes and Arp2/3-driven actin polymerization. Lateral accumulation of cadherin fingers in follower cells precedes turning, and increased actomyosin contractility can initiate cadherin finger extension as well as engulfment by a neighboring cell, to promote follower behavior. We propose that cadherin fingers serve as guidance cues that direct collective cell migration.

Receptor‐Free Signaling at Curved Cellular Membranes

“…[51] In recent work, we could show that the resulting positive feedback loop is sufficient to extend lamellipodial lifetime, and as a consequence, alter motion persistence and search pattern in motile cells. [55] Consistently, mice lacking the I-BAR domain protein BAIAP2 showed a delay in wound healing. [53] As members of the srGAP protein family sense similar curvatures, yet differ in the accompanying GAP domain, [54] differential expression of these proteins may yield altered functionalities across tissues.…”

VE-cadherin endocytosis controls vascular integrity and patterning during development

“…Classical cadherins have been implicated in polarization and collective cell movements by directing migration machinery and protrusive activity away from cell--cell contacts and towards the leading edge (Desai et al, 2009;Dupin et al, 2009;Theveneau et al, 2010;Weber et al, 2012). Although the mechanisms that promote cadherin--mediated polarization are poorly understood, they may involve anisotropic distribution of cadherin molecules or asymmetric signaling from cadherin--mediated junctions, which could be disrupted in the stabilized VE-cad DEE/DEE mutant (Dorland et al, 2016;Hayer et al, 2016;Mayor and Etienne--Manneville, 2016). Previous studies have implicated cadherin treadmilling along lateral borders, as well as endocytosis and recycling, in the process of collective cell migration (Peglion et al, 2014).…”

Practical Fluorescence Reconstruction Microscopy for Large Samples and Low-Magnification Imaging

“…Finally, we trained the network with VE-Cadherin:YFP data in an attempt to reconstruct not only 248 cellular borders, but also the well-characterized, nano-scale membrane fingers that develop in 249 endothelial cell-cell junctions and indicate the direction of front-rear polarity in each cell 30 . In 250 contrast to the actin performance, FRM proved far more capable here and readily detected both 251 general VE-Cadherin boundaries (Fig.…”

“…For instance, P = 28 0.7 lacks any practical context, and may be quite good enough for a given use case without 29 requiring more work to raise the 'accuracy'. This is why context is extremely important for FRM 30 and why the work we present here focuses on evaluating practical uses of FRM with respect to 31 given P values. 32 33 Our goal here is not to improve FRM performance, but rather to provide a standardized 34 implementation of it and demonstrate its practical performance for every-day tasks such as 35 nuclear localization and tracking, characterizing cell morphology, cell-cell junction detection and 36 analysis, and re-analyzing legacy data and data collected on different systems ( Fig.…”