View Program - 63rd Annual Drosophila Research Conference

I will be describing my lab’s work on cell competition and its physiological functions in Drosophila. Cell competition is the elimination of cells within an organ that only occurs when other cells are available to replace them. The term was originally coined to describe the elimination of ‘Minute’ (ie Rp/+) cells from mosaic imaginal discs containing wild type cells, which are progressively lost even though entirely Rp/+ animals are viable. Cell competition was originally envisaged as a homeostatic process responding to variations in cellular growth rate, but is now thought to provide a selection against abnormal cells that may arise in developing tissues. We used genetic screens to isolate mutations preventing cell competition. Analyzing these mutations changed how we think about the Minute phenotype, which iis now understood mostly to reflect a transcriptional response mediated by Xrp1, the key transcription factor that is expressed in Minute mutants. Remarkably, mutating this single transcription factor prevents cell competition and even restores normal overall translation to Minute cells. Minutes reduce translation though Xrp1-dependent phosphorylation of eIF2a by PERK, a kinase that also responds to ER stress, and not by reduction in ribosome numbers. Cell competition mutations do not affect organ size or reproducibility, instead they prevent certain kinds of abnormal cells from being eliminated. For example, aneuploid cells can be eliminated by cell competition on the basis of their abnormal Rp gene dose. Xrp1 seems also to be a common target of other cellular defects that trigger cell competition, including defects in ubiquitylation and protein turnover. Curiously, Xrp1 is a very rapidly evolving gene, which suggests it is involved in some evolutionary arms race, eg with pathogens. Interestingly, Xrp1 was first identified as a transcriptional target of p53 in the DNA damage response. Consistent with this, cells with different p53 activity levels compete with one another in imaginal discs. Notably, in mammalian cells Rp mutations lead to p53 activation, and there are multiple examples where different p53 activity levels lead to competition between mammalian cells. This suggests that aspects of mammalian p53 function may have been acquired by a p53 target gene in Drosophila, and leads us to speculate about how cell competition might contribute to cancer surveillance and tumor suppression.

Minute mutations, cell competition, and cellular surveillance