Experiments in both vertebrates and invertebrates have illustrated the competitive nature of growth and led to the idea that competition is a mechanism of regulating organ and tissue size. We have assessed competitive interactions between cells in a developing organ and examined their effect on its final size. We show that local expression of the Drosophila growth regulator dMyc, a homolog of the c-myc protooncogene, induces cell competition and leads to the death of nearby wild-type cells in developing wings. We demonstrate that cell competition is executed via induction of the proapoptotic gene hid and that both competition and hid function are required for the wing to reach an appropriate size when dMyc is expressed. Moreover, we provide evidence that reproducible wing size during normal development requires apoptosis. Modulating dmyc levels to create cell competition and hid-dependent cell death may be a mechanism used during normal development to control organ size.

Developing tissues that contain mutant or compromised cells present risks to animal health. Accordingly, the appearance of a population of suboptimal cells in a tissue elicits cellular interactions that prevent their contribution to the adult. Here we report that this quality control process, cell competition, uses specific components of the evolutionarily ancient and conserved innate immune system to eliminate Drosophila cells perceived as unfit. We find that Toll-related receptors (TRRs) and the cytokine Spätzle (Spz) lead to NFκB-dependent apoptosis. Diverse “loser” cells require different TRRs and NFκB factors and activate distinct pro-death genes, implying that the particular response is stipulated by the competitive context. Our findings demonstrate a functional repurposing of components of TRRs and NFκB signaling modules in the surveillance of cell fitness during development.

Summary Kinase Translocation Reporters (KTRs) are genetically encoded fluorescent activity sensors that convert kinase activity into a nucleocytoplasmic shuttling equilibrium for visualizing single cell signaling dynamics. Here, we adapt the first generation KTR for extracellular signal-regulated kinase (ERK) to allow easy implementation in vivo. This sensor, “ERK-nKTR,” allows quantitative and qualitative assessment of ERK activity by analysis of individual nuclei, and faithfully reports ERK activity during development and neural function in diverse cell contexts in C. elegans. Analysis of ERK activity over time in the Vulval Precursor Cells (VPCs), a well-characterized paradigm of EGFR-Ras-ERK signaling, has identified dynamic features not evident from analysis of developmental endpoints alone, including pulsatile, frequency-modulated signaling associated with proximity to the EGF source. The toolkit described here will facilitate studies of ERK signaling in other C. elegans contexts, and the design features will enable implementation of this technology in other multicellular organisms.

Summary In growing tissues, cell fitness disparities provoke interactions that promote stronger cells at the expense of the weaker in a process called cell competition. The mechanistic definition of cell fitness remains unclear, as does how differences are recognized. In Drosophila cells with extra Myc activity acquire “super-competitor” status upon confrontation with wild-type (WT) cells, prompting the latters’ elimination via apoptosis. Confrontation enhances Myc cell fitness by increasing glycolytic flux and promoting expansion of the population. p53 is induced in these cells and promotes their enhanced metabolism. Whereas p53 loss in noncompeting Myc cells is inconsequential, it impairs metabolism, reduces viability and prevents the killing activity of Myc super-competitor cells. We propose that p53 acts as a general sensor of competitive confrontation to enhance the fitness of “winner” cells. Our findings suggest that the initial confrontation between pre-cancerous and WT cells could enhance cancer cell fitness and promote tumor progression.