JNK-independent Eiger/TNFR signaling during cell competition
Authors: Aditi Sharma Singh; Laura A. Johnston
Affiliation: Columbia University Medical Center, New York, NY
Keywords: h. other (Cell competition); g. NF-kB signaling
Cell competition is a surveillance mechanism that promotes tissue/organ fitness by allowing healthy cells to contribute to organ development at the expense of cells that are relatively less fit. Such competitive interactions can benefit the tissue by eliminating unhealthy cells, but can also be detrimental when oncogenic cells take over an otherwise healthy tissue in a process known as super-competition. We have developed a model of super-competition using Drosophila wing imaginal discs, wherein cells over-expressing the proto-oncogene Myc (“winners”) compete for space with wild-type (WT) cells (“losers”) during the rapid growth phase of larval development. In this model, the death and elimination of WT loser cells from the wing disc is mediated by cell-cell interactions that activate a cell competition signaling module (CCSM) in loser cells, consisting of Toll-related receptors, the secreted ligand Spaetzle, and NF-kappaB proteins. Our recent genetic evidence indicates that Eiger (Egr), the sole TNF in Drosophila, and its cognate receptor, Grindelwald (Grnd)/TNFR, also contribute to the elimination of WT loser cells. Egr/Grnd signaling requires the TNFR adaptors Traf4/6 to kill the loser cells, but not Tak1 or other canonical downstream JNK effectors, indicating that in the competitive context, Egr functions independently of JNK activity. Moreover, although Grnd is expressed in all wing disc cells, in-vivo studies with Egr reporters and GFP fusion proteins reveal no evidence of Egr expression in either loser or winner cells. However, Egr, produced as both a secreted and transmembrane protein, is expressed in multiple tissues in growing larvae, so could remotely contribute to loser cell elimination. To determine which cells/tissues produce Egr during cell competition, we are selectively depleting egr from each expressing tissue while concomitantly inducing competitive interactions in wing discs. In addition, we are carrying out experiments to determine the mechanism by which Egr/Grnd activity intersects with the CCSM. Our experiments will provide insight into how local and remote signals converge to influence cell-cell interactions in the growing wing disc during Myc induced super-competition.