Ecdysteroid-DopEcR signaling in neuronal and midgut cells mediates toxin avoidance and detoxification in Drosophila.

Food is not only a source of nutrition but can also contain toxic substances. To survive, animals first need to avoid the ingestion of such harmful food, and if ingestion occurs, activate detoxification. However, the molecular coordination of these two functions has remained unclear. Using Drosophila melanogaster, we show that the major insect steroid hormone ecdysteroid and dopamine/ecdysteroid receptor (DopEcR) signaling play pivotal roles in both behavioral avoidance and detoxification of foods containing lethal levels of copper. Cell-type-specific knockdown experiments revealed that DopEcR signaling in neuronal cells mediates feeding aversion, while in the midgut copper cell region (CCR), it protects against copper toxicity. Upon copper ingestion, DopEcR in the CCR induces the expression of metallothionein (Mtn), a widely known detoxification protein. Furthermore, DopEcR mutants also failed to avoid and mitigate the effects of other hazardous substances such as paraquat and cocaine, suggesting a general role for DopEcR signaling in toxic food responses. This study demonstrates a cell-type-specific functional dissociation of ecdysteroid-DopEcR signaling for behavioral and physiological defenses against toxic foods.