Spatially Restricted Regulation of Spätzle/Toll Signaling during Cell Competition

Abstract

Cell competition employs comparisons of fitness to selectively eliminate cells sensed as less healthy. In Drosophila, apoptotic elimination of the weaker "loser" cells from growing wing discs is induced by a signaling module consisting of the Toll ligand Spätzle (Spz), several Toll-related receptors, and NF-κB factors. How this module is activated and restricted to competing disc cells is unknown. Here, we use Myc-induced cell competition to demonstrate that loser cell elimination requires local wing disc synthesis of Spz. We identify Spz processing enzyme (SPE) and modular serine protease (ModSP) as activators of Spz-regulated competitive signaling and show that "winner" cells trigger elimination of nearby WT cells by boosting SPE production. Moreover, Spz requires both Toll and Toll-8 to induce apoptosis of wing disc cells. Thus, during cell competition, Spz-mediated signaling is strictly confined to the imaginal disc, allowing errors in tissue fitness to be corrected without compromising organismal physiology.

The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner

“…After developmental time, indicated in the cartoon with a clock, clones of orange Toll OE cells are growing over a larger percentage of the tissue upon infection (A' and B'). The source of active Spätzle may be both systemic, as suggested by our experiments, and local (20).…”

“…Overexpression (OE) of Cactus in loser cells rescues cell competition-driven elimination of both RpL14 +/-Minute clones and of wild-type clones surrounded by cells with an extra copy of the dMyc gene (16). It has recently been proposed that dMyc-expressing winner cells release Spätzle and the serine proteases required for its activation, thereby enhancing Toll-dependent apoptosis in neighboring loser cells (20).…”

“…Likely therefore, the active form of Spätzle is produced in distant organs and reaches the wing disc through the haemolymph. However, it has recently been proposed that wing discs locally produce Spätzle and the serine proteases responsible for its activation (20). Via an increased secretion of these factors, Myc OE cells may be able to induce Toll-dependent apoptosis in neighboring loser cells (20).…”

“…However, it has recently been proposed that wing discs locally produce Spätzle and the serine proteases responsible for its activation (20). Via an increased secretion of these factors, Myc OE cells may be able to induce Toll-dependent apoptosis in neighboring loser cells (20). It is therefore possible that local and systemic sources of Spätzle co-exist.…”

Cell competition: the winners and losers of fitness selection

“…Finally, the observation that components of innate immunity pathways are required for the elimination of defective cells in Drosophila has led to the hypothesis that this mechanism, which is involved in host defence from foreign or altered-self cells, can be repurposed to eliminate less-fit cells (Alpar et al, 2018;Meyer et al, 2014). The authors of Meyer et al's study observed that, during cell competition, there is a repurposing of Toll-related receptors and NFκB factors, and this repurposing is required for the elimination of losers in Myc-and Minute-induced competition models.…”