During the development of an organism, the continued maintenance of determined cell fates is contingent upon the stability of networks of gene expression. Classical experiments using disc transplantation by Ernst Hadorn discovered the phenomenon of transdetermination in regenerating Drosophila imaginal discs. Damaged discs do not always regenerate the appropriate structures, and occasionally generate tissue appropriate for other discs or other parts of the same disc. Transdetermination results when cells with one determined state switch to a different determined state. Some signaling pathways, including Wg and Dpp have been shown to be important for this process. However, the underlying events that cause damage-induced transdetermination remain largely unknown, including the genes that regulate this process and the source of cells that change fate.
To address this question, we have conducted a deficiency screen for modifiers of regeneration that lead to the appearance of inappropriate structures following the ablation of the wing pouch by the temporally and spatially controlled expression of the TNF-alpha homolog eiger. Using this screen, we identified multiple loci that significantly increase the frequency of transdetermination. From one such locus, we identified the responsible gene as C-terminal Binding Protein (CtBP), which encodes for a transcriptional co-repressor that interacts with many different transcription factors. Inactivating mutations in the CtBP gene result in a high frequency of notum-to-wing transdetermination following damage, indicating that CtBP functions to maintain cell-fate identity during imaginal disc regeneration. The notum-to-wing fate change occurs following the generation of a secondary or ectopic blastema in the notum that is dependent on JNK activity. The new wing pouch arises from multiple cells and grows near the boundary that separates the anterior and posterior compartments, which is reminiscent of normal wing pouch development and suggests that cells at specific locations of the notum are more prone to undergo transdetermination into wing-pouch fated cells. In addition, during transdetermination multiple cells of the notum can also re-specify their compartmental identities, which under normal conditions are stably maintained. We have also observed that notum-to-wing transdetermination is significantly enhanced by increased expression of the cytokine Unpaired, and suppressed by reducing STAT activity, thereby demonstrating a role for the JAK/STAT pathway in triggering cell-fate plasticity. Taken together, our studies indicate that CtBP stabilizes cell fates and limits cell plasticity during regeneration and, especially when CtBP levels are reduced, damage-induced activation of JNK and JAK/STAT signaling can promote cell-fate plasticity and respecification.