Molecular mechanisms of cell competition in Drosophila melanogaster

Abstract

Cell competition can be observed when genetically distinct populations of cells share the same developing compartment. In cell competition, one population (winners) progressively kills the other population (losers) in a manner that depends on apoptosis of the loser cells. During competition between wild-type cells and cells heterozygous for certain ribosomal protein genes (termed Minutes), Minute cells at clone boundaries with wild-type cells undergo cell death. My work is focused on the cell death that occurs during competitive interactions between wild type and Minute cells.;Proteins of the cysteine protease family, caspases, govern apoptosis. In Drosophila, there are three apical caspases; Dronc, Dredd and Dream. Dronc mediates most cell death in Drosophila. My work has found that cell death in cell competition is mediated by caspases Dronc and Dream redundantly. su(Comp)3L-1 and su(Comp)3L-2 mutations are homozygous viable with no obvious developmental phenotype but prevent out-competition of Minute cells. We have mapped su (comp) 3L-1 to the RpS12 gene locus, encoding rpS12G97D. When neighboring Minute cells express varying levels of the RpS12 protein, those cells with higher levels are out-competed by those with lower levels, These results indicate that RpS12 levels determine the competitiveness of Minutes and may have a novel function as an effector for ribosomal stress that triggers cell competition. We have identified four candidates for the su(comp)3L-2 mutation. My studies have shown that, like RpS12, Su(comp)3L-2 gene dose also determines the competitiveness of Minute cells. Initial analysis suggests that su(comp)3L-2 might be a mutation in a protein that encodes the Ran-GEF.;Neighboring cells re-orient their mitoses in response to competitive apoptosis. My studies indicated that this process of re-orientation is governed by a subset of planar cell polarity pathway (PCP) proteins. When PCP proteins are removed from cells undergoing compensatory proliferation, they no longer reorient their mitosis towards their dying neighbors. These results showed that planar cell polarity pathway proteins in neighboring cells govern re-orientation of mitosis in response to competitive apoptosis.;In conclusion, the studies outlined in thesis establish that cell competition is a novel form of cell death, partly in response to ribosomal stress that provokes a homeostatic response from neighboring cells.