3) Cell competition
The phenomenon of cell competition was uncovered in studies of Drosophila imaginal discs and illustrates a remarkable feature of cells - that cell survival is based, not only on the intrinsic properties of the cell or of surrounding cells, but on a comparison of the properties of a cell to those of its neighbors. A class of mutations, known as Minutes (M), that are mostly in ribosomal proteins, dominantly and autonomously reduce cellular growth rates. Animals composed entirely of M/+ cells develop to the adult stage more slowly, but are of relatively normal size. However, clones of M/+ cells generated within wild-type imaginal discs are eliminated during development by apoptosis (Morata and Ripoll, 1975, Moreno et al., 2002). Conversely, wild-type cells can be eliminated when they are adjacent to faster-growing cells that overexpress Myc or have inactivating mutations in components of the Hippo-Salvador-Warts (HSW) pathway (known as “supercompetitors”). This progressive and selective elimination of a certain cell type by another is thought to be caused by short-range interactions at the boundaries between the two populations. In addition to cell competition, there are several other known instances in which short-range interactions nonautonomously influence cell survival, independent of growth rates(e.g. morphogenic apoptosis). None of these mechanisms is well understood. Especially enigmatic is the observations that many instances of cell competition occur between populations that have differences in levels of specific intracellular proteins. How can cells compare the levels of an intracellular protein between themselves and their neighbors?
We have found that apoptosis is observed preferentially at boundaries that separate populations of cells that express different levels of the transmembrane protein Crumbs (Crb). We also observed distortions in the structure of epithelia on either side of boundaries between populations of cells that differ in Crb expression. Thus, while previous studies have focused mostly on the cell autonomous functions of Crb, we found that Crb can regulate cell survival and tissue morphology nonautonomously. Moreover, the extracellular domain (ECD) of Crb, which seems to be dispensable for some of the other characterized functions of Crb, is required to elicit the nonautonomous effects on cell survival. The ECD can also regulate the subcellular localization of Hippo pathway components, and possibly other proteins, in adjacent cells and may therefore directly mediate these effects. Several genetic lesions that alter the competitive ability of cells alter Crb levels, including loss-of-function mutations in hyperplastic tumor suppressors in the Hippo-Salvador-Warts pathway and in neoplastic tumor suppressor genes, such as scribble. Thus, Crb may be part of a “surveillance mechanism” where cells compare themselves to their neighbors; differences in Crb levels could account for the cell death that is observed at clonal boundaries in certain types of heterotypic interactions.
Hafezi Y, BoschJA, Hariharan IK (2012) Differences in levels of the transmembrane protein Crumbs can influence cell survival at clonal boundaries Developmental Biology 368:358-369. (PubMed Link)
We present a model where aymmetric localization of Crb prediposes cells at the boundary to undergo apoptotic cell death.