Genes Affecting Cell Competition in Drosophila

Abstract

Cell competition is a homeostatic mechanism that regulates the size attained by growing tissues. We performed an unbiased genetic screen for mutations that permit the survival of cells being competed due to haplo-insufficiency for RpL36. Mutations that protect RpL36 heterozygous clones include the tumor suppressors expanded, hippo, salvador, mats, and warts, which are members of the Warts pathway, the tumor suppressor fat, and a novel tumor-suppressor mutation. Other hyperplastic or neoplastic mutations did not rescue RpL36 heterozygous clones. Most mutations that rescue cell competition elevated Dppsignaling activity, and the Dsmurf mutation that elevates Dpp signaling was also hyperplastic and rescued. Two nonlethal, nonhyperplastic mutations prevent the apoptosis of Minute heterozygous cells and suggest an apoptosis pathway for cell competition . In addition to rescuing RpL36 heterozygous cells, mutations in Warts pathway genes were supercompetitors that could eliminate wild-type cells nearby. The findings show that differences in Warts pathway activity can lead to competition and implicate the Warts pathway, certain other tumor suppressors, and novel cell death components in cell competition, in addition to the Dpp pathway implicated by previous studies. We suggest that cell competition might occur during tumor development in mammals.

Tumor suppression by cell competition through regulation of the Hippo pathway

“…Thus, loss of Hippo pathway activity or elevated levels of Yki activity result in hyperproliferation of imaginal disc cells and resistance to apoptosis that normally would eliminate extra cells (21). Notably, an increase in Yki activity can rescue weak cells, such as cells heterozygous for Minute (M) mutations, from being eliminated by cell competition (22). M mutations occur in ribosomal proteinencoding genes and were the first class of genes identified as having cell-competition phenotypes (23).…”

The Active Role of Corpse Engulfment Pathways During Cell Competition

“…For example there is differing data concerning the degrees to which Dpp is a survival signal or Jun Kinase activity required for competitive cell death. 5,7,[9][10][11] It has been suggested that Myc levels could also affect Dpp capture. 6 However, other workers have proposed that cells with higher Myc might send a non-autonomous killing signal that is independent of Dpp.…”

“…Screens have previously been performed to identify genes that are needed in the cells that lose competitions. 7,9 …”

“…Interestingly, quantitatively different effects are seen surrounding small and large territories mutant for Warts-Pathway genes. 7 It has previously been suggested that the Warts Pathway may be connected to tension because Merlin encodes an actin-binding protein, implicated in contact inhibition in mammalian cells. 25 cELL compEtItIoN: WhAt Is It good for?…”

“…Clones of hyperplastic, Warts-Pathway mutant cells kill neighboring wild-type cells in a competition-like manner, although it has not yet been determined whether there is a reciprocal growth enhancement of the Warts-Pathway mutant cells, as occurs in true cell competition. 7 Recently, we described an essential role for corpse engulfment pathway genes in cell competition. 8 The purpose of this Extra View article is to summarize these findings, accompanied by expanded discussion of the possible implications for the initiation and progress of cell competition.…”