Fine tuning of cell death during epithelial homeostasis: from local coordination to death commitment and cell extrusion
While the signals regulating apoptosis during development are rather well known, what regulates the precise spatio-temporal distribution of cell death and the adjustment of cell elimination to local perturbations is not well understood. Similarly, how cells eventually engage in apoptosis and how the removal of cells from epithelial layer is orchestrated through cell extrusion remained poorly understood, especially in vivo. In this seminar, I will present two recent studies illustrating our attempt to dissect these two layers of regulation.
I will first illustrate how tissue can adapt to high rates of cell elimination by modulating the spatiotemporal distribution of cell death through local feedbacks. Using the Drosophila pupal notum (a single layer epithelium), optogenetics control of caspases, statistical analysis of cell elimination with live sensor of signaling pathways, we showed that local pulses of EGFR/ERK triggered by cell death inhibit transiently caspase activation in neigbouring cells, hence preventing the concomitant elimination of group of cells. This work highlights how tissue robustness and plasticity can emerge from local and transient feedbacks.
In the second part, I will present our recent attempt to characterize the process of cell extrusion in the pupal notum. We previously showed that caspases activation precede and is required for cell extrusion in the notum, however it remained unclear how caspases would regulate cell extrusion. Contrary to other morphogenetic processes, we characterized an early phase of cell apical constriction which is not associated with any changes of actomyosin concentration/dynamics/activity nore a modulation of cell-cell adhesion. Surprisingly, the initiation of cell extrusion is rather associated with an early disassembly of a medio-apical mesh of microtubules (MTs), which is triggered by caspase activation. Accordingly, we found that MTs modulation is sufficient to transiently modulate cell apical area, while MTs depletion is sufficient to bypass the inhibtion of caspases and restore cell extrusion. This work highlight an important role of MTs for the stabilization of cell apical area which may be relevant in other morphogenetic processes.
Department of Developmental and Stem Cell Biology, Paris, France