Here we show that tissue compaction induces cell elimination

Here, we show that tissue compaction induces cell elimination in the pupal notum through the downregulation of epidermal growth factor receptor/extracellular signal regulated kinase (EGFR/ERK) pathway and the upregulation of the pro-apoptotic protein Hid (head involution defective). Using a new Drosophila live sensor of ERK activity, we demonstrate that local tissue stretching or compaction transiently upregulate or downregulate ERK activity, hence increasing or decreasing cell survival. Moreover, we show that compaction-driven ERK downregulation near Ras-activated clones controls cell elimination and promotes clone expansion. The sensitivity of EGFR/ERK pathway to mechanics and its role in the fine tuning of cell elimination could play a more general role during tissue homeostasis and tumor progression.
Results
Discussion EGFR/ERK/Hid pathway has been previously involved in tissue homeostasis and cell number regulation [44, 45]. For instance, modulation of segment size in Drosophila embryo can be adjusted by cell death regulated by EGFR/Hid and the limited source of Spitz/EGF [45, 46]. A similar mechanism is involved in the regulation of the number of interommatidial CGP 57380 sale in the fly retina [19, 47, 48, 49, 50] or the number of glia cells in the embryo [51]. Those studies are based on the modulation of EGFR/ERK and death triggered by limiting extracellular ligands. Here, we show that ERK activity can also be modified by tissue mechanics in vivo, which changes the probability of cell survival. Modulation of ERK activity by mechanical stress and/or tissue density has been previously described in cell culture [31, 33, 34, 36, 52] and in vivo [35]. Here, we provide the first evidence of a mechanical modulation of ERK playing an instructive role for cell survival and death during competitive interactions between two cell types in vivo. So far, most of the studies of mechanotransduction in vivo focused on the regulation of Hippo/Yap-Taz pathway [11], whose transcriptional outputs should act on hours timescale. Our results suggest that ERK modulation could act on cell survival in a few tens of minutes (see Figure 4) through the phosphorylation [18] and/or transcriptional regulation [19] of Hid. Interestingly, global EGFR depletion increased the rate of cell elimination everywhere in the notum (Figures 2B–2D), irrespective of the deformation status of the cells. Accordingly, we found that cells are not any more sensitive to stretching upon EGFR depletion (Figures S6A–S6C; Video S5). This suggests that a ubiquitous basal activity of EGFR is required for cell survival everywhere in the notum, which could be then modulated by tissue deformation. We found that tissue stress and/or compaction can modulate ERK activity and that part of the ERK dynamics correlated with tissue deformations. However, it is very likely that the complex spatiotemporal pattern of ERK activity in the pupal notum (e.g., global downregulation 16 or 17 hr APF and global upregulation 20 hr APF; Video S2) is also controlled by currently unknown patterning genes. EGFR/ERK modulation by deformation may be required to fine tune its activity, to coordinate in time and space cell elimination, and to regulate the number of cells that will be eliminated. A high rate of cell elimination could lead to higher cell spacing and/or an increase of tissue tension, which would feedback negatively on cell elimination through ERK activation. Moreover, the mutual regulation of ERK and mechanics [30, 31, 32] could generate complex temporal dynamics and self-organized properties [31].