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Role of Epithelial Apoptotic Force in Morphogenesis

Description du projet

Le rôle dynamique des cellules mourantes dans la morphogenèse

Au cours du développement, des modèles ordonnés et le plan corporel final sont formés dans une cascade de processus collectivement appelés morphogenèse. L’apoptose, ou mort cellulaire programmée, est considérée comme un moyen d’éliminer les cellules indésirables, soutenant passivement la morphogenèse. De récentes études suggèrent que les cellules apoptotiques peuvent jouer un rôle dynamique d’importance au cours de la morphogenèse, mais les mécanismes demeurent inconnus. Financé par le Conseil européen de la recherche, le projet EPAF tentera de déterminer les mécanismes cellulaires à l’origine de la récente découverte selon laquelle les cellules apoptotiques exercent une force de traction sur les cellules épithéliales de la patte en développement de la drosophile, entraînant le plissement de l’épithélium. Les chercheurs du projet compareront ensuite la dynamique apoptotique à d’autres processus d’extrusion cellulaire, tels que la transition épithélio-mésenchymateuse, afin d’en étudier les similitudes et les différences.

Objectif

Contrary to previous beliefs, recent studies have suggested that apoptotic cells play an important dynamic role during morphogenesis. Nonetheless, the mechanisms whereby dying cells drive tissue shape modification remain elusive.
Using the Drosophila developing leg as a model system to study apoptosis-dependent epithelium folding, we have recently shown that apoptotic cells produce a pulling force through the unexpected maintenance of their adherens junctions that serves as an anchor to an apico-basal Myosin II cable. The resulting apoptotic apico-basal force leads to a non-autonomous increase in tissue tension and apical constriction of surrounding cells, leading to epithelium folding. These results reveal that, far from being passively eliminated as generally thought, dying cells are very active until the end of the apoptotic process. The objective of the present proposal is to understand how apoptotic cells influence their surroundings from the micro-environment to the macro-scale level.
Our first aim is to dissect the cellular mechanisms governing the generation of the apoptotic force and its transmission to the tissue, both apically through planar polarity and basally through the extra-cellular matrix (ECM), in parallel with the identification of the network of genes orchestrating apoptosis-dependent morphogenesis through a powerful genetic screen. Interesting preliminary results have already identified the epithelio-mesenchymal-transition gene Snail as essential for the progression of apoptosis, thus validating our approach.
Therefore, the second aim of this project is to compare Snail function in the control of adhesion and ECM dynamics and in the generation of tissue tension in both EMT and apoptosis. This original comparative study should bring novel insight into these two fundamental processes.

To perform this work, we will use elegant genetic tools combined to state-of-the-art live imaging techniques, together with robust biophysical modelling.

Régime de financement

ERC-COG - Consolidator Grant

Institution d’accueil

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Contribution nette de l'UE
€ 2 311 843,75
Adresse
RUE MICHEL ANGE 3
75794 Paris
France

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Région
Ile-de-France Ile-de-France Paris
Type d’activité
Research Organisations
Liens
Coût total
€ 2 311 843,75

Bénéficiaires (1)