Soluble factors mediate competitive and cooperative interactions between cells expressing different levels of Drosophila Myc

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Abstract
When neighboring cells in the developing Drosophila wing express different levels of the transcription factor, dMyc, competitive interactions can occur. Cells with more dMyc proliferate and ultimately overpopulate the wing, whereas cells with less dMyc die, thereby preventing wing overgrowth. How cells sense dMyc activity differences between themselves and the nature of the process leading to changes in growth and survival during competition remain unknown. We have developed a cell culture-based assay by using Drosophila S2 cells to investigate the mechanism of cell competition. We find that in vitro coculture of S2 cells that express different levels of dMyc leads to cellular interactions that recapitulate many aspects of cell competition in the developing wing. Our data indicate that both cell populations in the cocultures participate in and are required for the competitive process by releasing soluble factors into the medium. We demonstrate that the response of naive cells to medium conditioned with competitive cocultures depends on their potential to express dMyc: Cells that can express high levels of dMyc gain a survival advantage and proliferate faster, whereas cells with lower dMyc levels are instructed to die. We suggest that the ability of cells to perceive and respond to local differences in Myc activity is a cooperative mechanism that could contribute to growth regulation and developmental plasticity in organs and tissues during normal development and regeneration.