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

Authors :
Valon, Léo
Davidović, Anđela
Levillayer, Florence
Villars, Alexis
Chouly, Mathilde
Cerqueira-Campos, Fabiana
Levayer, Romain
Cellules Souches et Développement / Stem Cells and Development
Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Département de Biologie Computationnelle - Department of Computational Biology
Collège Doctoral
Sorbonne Université (SU)
L.V. is supported by a postdoctoral grant 'Aide au Retour en France' from the FRM (Fondation pour la Recherche Médicale, ARF20170938651) and a Marie Sklodowska-Curie postdoctoral fellowship (MechDeath, 789573), and work in R.L.’s lab is supported by the Institut Pasteur (G5 starting package), the ERC starting grant CoSpaDD (Competition for Space in Development and Disease, grant number 758457), and the Cercle FSER, and the CNRS (UMR 3738).
We thank members of R.L.’s lab for critical reading of the manuscript, especially Alexis Matamoro-Vidal for suggestions on the manuscript organization. We would like to thank Jakub Voznica for initiating observations of miniCic in the pupal abdomen during his internship and Anne Loap for her contribution to tissue segmentation and caspase dynamics analysis during her internship. We also thank Virgile Andreani for help in improving simulations, statistical analysis of the data, and some mathematical expressions. We are grateful for the image analysis center of Pasteur Institute and Jean-Yves Tinevez for converting the local-projection program to Fiji. We are also grateful to Magali Suzanne, Yohanns Bellaïche, Shigeo Hayashi, Jared Toettcher, the Bloomington Drosophila Stock Center, the Drosophila Genetic Resource Center, and the Vienna Drosophila Resource Center for sharing stocks and reagents. We also thank B. Aigouy for the Packing Analyser software and the J. Ellenberg group for MyPic autofocus macro.
European Project: 758457,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),ERC-2017-STG,CoSpaDD(2018)
Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Collège doctoral [Sorbonne universités]
Mort cellulaire et homéostasie des épithéliums / Cell death and epithelial homeostasis
Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
Source :
Developmental Cell, Developmental Cell, 2021, ⟨10.1016/j.devcel.2021.05.006⟩, Developmental Cell, Elsevier, 2021, ⟨10.1016/j.devcel.2021.05.006⟩, Developmental Cell, 2021
Publication Year :
2020

Abstract

Summary What regulates the spatiotemporal distribution of cell elimination in tissues remains largely unknown. This is particularly relevant for epithelia with high rates of cell elimination where simultaneous death of neighboring cells could impair epithelial sealing. Here, using the Drosophila pupal notum (a single-layer epithelium) and a new optogenetic tool to trigger caspase activation and cell extrusion, we first showed that death of clusters of at least three cells impaired epithelial sealing; yet, such clusters were almost never observed in vivo. Accordingly, statistical analysis and simulations of cell death distribution highlighted a transient and local protective phase occurring near every cell death. This protection is driven by a transient activation of ERK in cells neighboring extruding cells, which inhibits caspase activation and prevents elimination of cells in clusters. This suggests that the robustness of epithelia with high rates of cell elimination is an emerging property of local ERK feedback.<br />Graphical abstract<br />Highlights • Simultaneous elimination of three neighboring cells is detrimental for epithelia • Biased cell-death distribution prevents the appearance of such clusters • This bias is driven by ERK pulses and caspase inhibition in the neighbors of dying cells • Clusters of elimination and transient sealing defects appear upon EGFR/ERK inhibition<br />How epithelia fine-tune the spatiotemporal distribution of cell death and cope with high rates of elimination remains unclear. Valon et al. shows that pulses of ERK induced near every dying cell prevent the simultaneous elimination of neighboring cells, hence maintaining epithelial sealing despite the high rates of cell elimination.

Details

ISSN :
18781551 and 15345807
Volume :
56
Issue :
12
Database :
OpenAIRE
Journal :
Developmental cell
Accession number :
edsair.pmid.dedup....aee9bdc1e4728e9147f98b68da4847c5
Full Text :
https://doi.org/10.1016/j.devcel.2021.05.006⟩