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Spatial Integration in Cell Cytoskeleton

Final Report Summary - SPICY (Spatial Integration in Cell Cytoskeleton)

It is important that cells organize themselves in a coherent manner in tissues to ensure proper tissue functions. Cells sense where their neighbors are and adapt their architecture and polarity accordingly. The aim of our project is to investigate how cells build their internal architecture with respect to the geometry of their environment. In particular it is about the intra-cellular mechanism directing the self-organization of cytoskeleton networks, the actin filaments and the microtubules, in response to defined geometrical boundary conditions.

First, both actin and microtubule networks were studied separately. We found that actin filament cross-linkers are central to the propagation of mechanical forces within the actin network and the establishment of a geometrical and mechanical balance that is adapted to external cues. In parallel we found that microtubules, which were known to be very rigid filaments, have much more complex structural and mechanical properties than we thought. They could become softer when submitted to external forces, but more surprisingly, they were able to self-repair and recover their original stiffness. Thus, the dynamic of monomer exchange is not limited to microtubule ends but can happen all along the shaft of the microtubule in response to various stimuli and notably mechanical forces.

Second, we studied the interplay between the two networks. They were known to have some interactions via some cross-linkers binding the two types of filaments. We discovered new modes of interaction. The two networks sterically block each others. Dense actin filaments networks, in meshwork at the cell front or in bundles in their ventral part, prevent microtubule growth. The centrosome, which is the central organelle from which microtubules are nucleated and radiate throughout the cell cytoplasm, is also able to nucleate actin filaments. Here also the two network compete and influence each others.

Finally we studied some conditions in which cell adapt to external changes by remodeling their architecture and polarity. We found that the centrosome and the microtubules modulate the strength of the cell-cell junction and that in return the junction directs centrosome position. We found that when epithelial cells, that are lining organs periphery, become mesenchymal cells and move inward to the organ interior, they completely revert their polarity. The centrosome, and the associated microtubule network, changes its position and relocalizes on the opposite cell side. Cells that were oriented toward the outside of the organ get thus oriented toward the inside. This was coupled to the reorganization of the actin cytoskeleton as well. As a result, cells disengage from their neighbours, leave the organ periphery and start moving inside. This can happen in physiological conditions, like during gastrulation, or during pathological transformation like cancer cell invasion. These results highlight how some large morphologic changes at the tissue scale are supported by precise intracellular remodeling of cytoskeleton networks which have amazing adaptative self-organization properties.