Calcium Wave Promotes Cell Extrusion

Takeuchi, Yasuto; Narumi, Rika; Akiyama, Ryutaro; Vitiello, Elisa; Shirai, Takanobu; Tanimura, Nobuyuki; Kuromiya, Keisuke; Ishikawa, Susumu; Kajita, Mihoko; Tada, Masazumi; Haraoka, Yukinari; Akieda, Yuki; Ishitani, Tohru; Fujioka, Yoichiro; Ohba, Yusuke; Yamada, Sohei; Hosokawa, Yoichiroh; Toyama, Yusuke; Matsui, Takaaki; Fujita, Yasuyuki

doi:10.1016/j.cub.2019.11.089

Cited by 80 publications

(70 citation statements)

References 35 publications

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“…Importantly, the mechanism we characterised in this study are conserved in mammals as similar ERK dynamics were observed near dying MCF10A cells which also generate transient resistance to apoptosis (personal communication, Olivier Pertz lab). Interestingly, other reports also described Ca 2+ and ERK activation waves emanating from extruding MDCK pretumoral cells or caspase-induced MDCK extrusion 18,19 . However in these cases the waves rather promote extrusion of the dying/extruding cells through collective convergent movements.…”

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confidence: 94%

Robustness of epithelial sealing is an emerging property of local ERK feedbacks driven by cell elimination

Valon

Levillayer

Davidović

et al. 2020

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10While the pathways regulating apoptosis and cell extrusion are rather well 11 described 1,2 , what regulates the precise spatio-temporal distribution of cell 12 elimination in tissues remains largely unknown. This is particularly relevant for 13 epithelia with high rates of cell elimination, a widespread situation during 14 embryogenesis 3-6 and homeostasis 7 , where concomitant death of neigbours could 15 impair the maintenance of epithelial sealing. However, the extent to which epithelial 16 tissues can cope with concomitant cell death, and whether any mechanism 17 regulates such occurrence have never been explored so far. Here, using the 18 Drosophila pupal notum (a single layer epithelium) and a new optogenetic tool to 19 trigger caspase activation and cell extrusion, we first show that concomitant death 20 of clusters of at least three cells is sufficient to transiently impair epithelial sealing. 21 Such clustered extrusion was almost never observed in vivo, suggesting the 22 existence of a mechanism preventing concomitant elimination of neighbours. 23 Statistical analysis of cell death distribution in the notum highlighted a transient 24 and local protective phase occurring near every dying cell. This protection is driven 25 by a transient activation of ERK in the direct neighbours of extruding cells which 26 reverts caspase activation and prevents elimination of cells in clusters. Altogether, 27 this study demonstrates that the distribution of cell elimination in epithelia is an 28 emerging property of transient and local feedbacks through ERK activation which 29 is required to maintain epithelial sealing in conditions of high rate of cell 30 elimination. 31 Epithelial cell elimination is driven by extrusion, a succession of remodeling steps 32 removing one cell from the epithelial layer while maintaining epithelial sealing 1,8 . We first 33 asked whether concomitant extrusion of several neigbours impairs the maintenance of 34 epithelial sealing. As such, we developed a UAS-optoDronc Drosophila line, which can 35 trigger rapid caspase activation through blue light-induced clustering of Caspase9 36 (Figure 1a, Figure S1a). Expression of optoDronc in fly eyes (GMR-gal4 eye-specific 37 driver) is sufficient to trigger cell death upon blue light exposure and can be rescued by 38 expression of the downstream effector caspase inhibitor p35 (Figure S1b). We then used 39 the Drosophila pupal notum to assess the efficiency of the construct in triggering epithelial 40 cell elimination. Blue light exposure of clones expressing optoDronc triggers elimination 41 of the majority of cells in less than one hour (Figure 1b, Figure S1c,e, movie S1). 42 OptoDronc-triggered extrusions are similar to physiological extrusions in the pupal notum, 43 albeit slightly faster (Figure S1f), and require effector caspase activation (Figure S1d,e, 44 movie S1) like physiological extrusions in the notum 9,10 . We then induced concomitant 45 elimination of group of cells of various sizes and shapes by expressing optoDronc in 46...

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confidence: 94%

Robustness of epithelial sealing is an emerging property of local ERK feedbacks driven by cell elimination

Valon

Levillayer

Davidović

et al. 2020

Preprint

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“…This design can confer stringency, so that extrusion is only triggered when an apoptotic event is clearly underway. It will therefore be interesting to see how this system for RhoA activation cooperates with other signals [32] and cytoskeletal regulators [9] to ensure that epithelia can rapidly eliminate apoptotic cells by apical extrusion.…”

Section: Supplementarymentioning

confidence: 99%

A unified view of neighbour cell engagement during apoptotic cell extrusion

Duszyc

Gómez

Lagendijk

et al. 2020

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Epithelia must eliminate apoptotic cells to preserve tissue barriers and prevent inflammation [1]. Several different mechanisms exist for apoptotic clearance, including efferocytosis [2, 3] and apical extrusion [4, 5]. We found that extrusion was the first-line response to apoptosis in cultured monolayers and in zebrafish epidermis. During extrusion, the apoptotic cell elicited active lamellipodial protrusions and assembly of a contractile extrusion ring in its neighbours. Depleting E-cadherin compromised both the contractile ring and extrusion, implying that a cadherin-dependent pathway allows apoptotic cells to engage their neighbours for extrusion. We identify RhoA as the cadherin-dependent signal in the neighbour cells and show that it is activated in response to contractile tension from the apoptotic cell. This mechanical stimulus is conveyed by a Myosin VI-dependent mechanotransduction pathway that is necessary both for extrusion and to preserve the epithelial barrier when apoptosis was stimulated. Earlier studies suggested that release of sphingosine-1-phosphate (S1P) from apoptotic cells might define where RhoA was activated. However, we found that although S1P is necessary for extrusion, its contribution does not require a localized source of S1P in the epithelium. We therefore propose a unified view of how RhoA is stimulated to engage neighbour cells for apoptotic extrusion. Here, tension-sensitive mechanotransduction is the proximate mechanism that activates RhoA specifically in the immediate neighbours of apoptotic cells, but this also must be primed by S1P in the tissue environment. Together, these elements provide a coincidence detection system that confers robustness on the extrusion response.

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“…Calcium wave and collective movements during cell extrusionAdapted from[15]. A: Cell extrusion is triggered in MDCK cells or zebrafish either by a transformed RasV12 cells surrounded by WT (EDAC) or through overexpression of Caspase-8.…”

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confidence: 99%