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Role of Epithelial Apoptotic Force in Morphogenesis

Periodic Reporting for period 3 - EPAF (Role of Epithelial Apoptotic Force in Morphogenesis)

Reporting period: 2018-09-01 to 2020-02-29

The overall goal of the project is to understand the forces allowing a tissue to progressively acquire its final shape during development. We focus particularly on cell rearrangements taking place when cell are eliminated from monolayer epithelium, either to be eliminated (apoptosis) or to migrate and integrate another tissue (epithelial-mesenchymal transition). We recently discovered that epithelial dying cells, before being eliminated, generate a force that increase tissue tension and by this way modify its shape. The questions we asked now is how this force is generated and transmitted to the neighboring tissue and if this force is specific of dying cells or could be generated in other contexts of cell delamination.
We know that mechanics is playing an important role in tissue dynamics both in physiological and pathological contexts and believe that this work will be of interest to a wide scientific community.
To understand how cell delamination affects epithelium remodeling, we follow the developing tissue in live and characterize the dynamic of force generating cells. To do so, we combine the powerful tools available in Drosophila with top of the art imaging techniques and biophysical approaches.
In a first part of the project, we are trying to identify what are the key players at the cellular level responsible for force generation. We recently identified a cellular mechanism responsible for force generation which involves the creation of a contractile structure of acto-myosin attached to a basally anchored nucleus, creating a basal resistance point to the force.
In the second part of the project, we tested if other cells than the dying ones could induce force during their extrusion. We discover that other type of delaminating cell could also actively influence their environment suggesting that epithelial cell extrusion could have a general impact in tissue tension and shape.
The data obtained so far reveal a new force generation mechanism highlighting a crucial role for the nucleus in force generation. Although the nucleus has a key role due to its genomic content and is known to respond to mechanical force, its involvement in force generation was totally unexpected.
Comparing different morphogenetic events, we revealed a striking similarity between dying cells and cell becoming mesenchymal and migratory at the time they are preparing to leave the epithelium. Both are pulling on the tissue and participate to its remodeling.
These works also support the idea that folding processes required not only apical constriction but also another set of forces generated perpendicular to the plane of the epithelium.
Altogether, this work open new avenues in the field of mechano-biology and will be of interest to an expanding community.
For the second part of this project, we plan to decipher how these force are transmitted to the tissue and what are the conditions allowing a long range or short range transmission of forces generated locally at the level of a few delaminating cells. We also want to address how a similar mechanism of force generation can be generated in processes having a very different outcome such as apoptosis and epithelial-mesenchymal transition.