Competition for space induces cell elimination through compaction-driven ERK downregulation

Abstract

13The plasticity of developing tissues relies on the adjustment of cell survival and growth rate to 14 environmental cues. This includes the effect of mechanical cues on cell survival. Accordingly, 15 compaction of an epithelium can lead to cell extrusion and cell death. This process was 16proposed to contribute to tissue homeostasis but also to facilitate the expansion of pretumoral 17 cells through the compaction and elimination of the neighbouring healthy cells. However we 18 know very little about the pathways than can trigger apoptosis upon tissue deformation and 19 the contribution of compaction driven death to clone expansion was never assessed in vivo. 20Using the Drosophila pupal notum and a new live sensor of ERK, we show that tissue 21 compaction induces cell elimination through the downregulation of EGFR/ERK pathway and 22 the upregulation of the pro-apoptotic protein Hid. Those results suggest that the sensitivity of 23 EGFR/ERK pathway to mechanics could play a more general role in the fine tuning of cell 24 elimination during morphogenesis and tissue homeostasis. Secondly, we assessed in vivo the 25 contribution of compaction driven death to pretumoral cell expansion. We found that the 26 activation of the oncogene Ras in clones can also downregulate ERK and activate apoptosis 27 in the neighbouring cells through their compaction, which contributes to Ras clone expansion. 28The mechanical modulation of EGFR/ERK during growth-mediated competition for space may 29 contribute to tumour progression. 30 31 32 33Developing tissues have the capacity to cope with perturbations, which include stress from the 34 environment (mechanical, chemical, temperature) as well as abnormal behaviors of a subset 35 of cells (misspecification, local modification of growth rate). This robustness relies on the 36 plasticity of cell behavior/fate which can be adjusted to changes in the tissue environment. The 37 adjustment of cell proliferation and cell death could rely on several inputs, including contact 38 dependent communication, communication through extracellular diffusive factors and/or 39 communication through mechanical inputs [1]. Accordingly, mechanical cues have been 40proposed to adjust the local rate of cell death and cell division to regulate the final size of a 41 tissue or to maintain constant size during homeostasis [2][3][4]. 42The regulation of cell death by mechanical inputs is well documented in epithelia. Compaction 43 of epithelia was shown to induce cell extrusion and cell death in MDCK cells, and in the midline region of the Drosophila pupal notum (a single layer epithelium) [8] ( Fig. 45 1A). Recently, we showed that compaction driven cell elimination in the pupal notum relies on 46 caspase activation which was required for and preceding every extrusion event [9]. This 47 suggested that some unknown pathways could be sensitive to tissue deformations and trigger 48 caspase activation. However, we could not find a clear contribution of known 49 mechanosensitive pathways to midline cell eliminatio...