Drosophila Myc regulates organ size by inducing cell competition

Experiments in both vertebrates and invertebrates have illustrated the competitive nature of growth, and led to the idea that competition amongst cells may be a mechanism of regulating organ and tissue size.  We have used the Drosophila imaginal wing disc to assess competitive interactions between cells of a developing organ and to test their role in regulating organ size.  In mosaic wing discs, cells deficient for the Drosophila growth regulator dmyc, a homolog of the c-myc proto-oncogene, grow very slowly and are competitively eliminated.  In this work, we show that increased expression of dMyc allows cells to out-compete otherwise viable wildtype cells, and ultimately leads to the death of their wildtype neighbors.  By analyzing this competitive interaction, we show that the effects of cell competition are executed via induction of the pro-apoptotic gene hid.  Expression of dMyc in small groups of cells fails to alter overall wing size.  However, the wing does overgrow when dMyc is expressed in all cells.  We provide evidence that wildtype clones generated in such discs are competitively eliminated, and that their removal allows the wing to approach its normal size.  Cell death is critical to this size regulation because under conditions in which dMyc is expressed in part of the wing disc, hid function is required to limit growth of the wing.  Interestingly, even during normal development, wing size is altered in the absence of hid, suggesting that cell death refines normal growth to produce precise, reproducible wing sizes.  Based on these studies, we propose that modulating dmyc levels to create cell competition and cause hid-dependent cell death may be a mechanism used during normal development to control organ size.