Spatial Integration in Cell Cytoskeleton
Start date: Dec 1, 2012,
End date: Sep 30, 2018
The functional coherence in multicellular arrangements depends on each cell’s ability to adapt its internal organisation to the spatial configuration of their microenvironment. The asymmetric distributions of cell compartments and peripheral domains define the cell polarity. In multicellular animals, the establishment of cell polarity is mainly regulated by the cell’s adhesions to its neighbours and to the surrounding extracellular matrix (ECM). How cells integrate all these cues in space and time to determine the orientation of their polarity is a fundamental but unresolved problem.I hypothesize that the centrosome, which regulates the radial organisation of microtubules throughout the cell, plays a major role in the spatial integration of peripheral adhesive cues. Each type of adhesion induces the assembly of actin filaments into defined dynamic architectures. These architectures produce specific mechanical forces on microtubules. The net force displaces the centrosome-microtubule network and thereby repositions cell compartments and orients cell polarity.I propose to develop a new experimental strategy to manipulate cell adhesions in space and time. Using surface micropatterning and a new laser activation method, the spatial organisation of cell-cell and cell-ECM adhesions in complex multicellular context will be manipulated in real-time. We will quantify the dynamic rearrangements of actin and microtubule networks and measure intracellular forces. These results will allow us to develop a new physical model describing the stability of cell polarisation states. Finally, in the context of this model, we will explore the contribution of polarity reversal to critical morphogenetic events.This work will demonstrate that cell polarisation is a dynamic and mechanical event that is not the final outcome of tissue morphogenesis but instead an active mechanism allowing cells to continually probe and reconfigure tissue architecture.
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