Outstretched wing is controlled by intestinal enteroblasts-derived unpaired 2 cytokine signaling in Drosophila.

The outstretched wing phenotype in Drosophila melanogaster can be induced by various genetic mutations and environmental perturbations, yet the role of gut-derived signals in coordinating wing development remains largely unexplored. In this study, we demonstrate that Upd2, secreted from the gut to the wing discs, plays a crucial role in regulating the outstretched wing phenotype. The intestinal precursor cell driver esg-Gal4 exhibits low levels of leaky expression, even in the presence of Gal80 at room temperature (25°C). This leaky expression of TDP-43, Notch, and Yki in intestinal precursor cells leads to a held-out wing phenotype, shortened lifespan, and impaired locomotor function. Although esg-Gal4 is expressed in imaginal discs, overexpression of TDP-43, Notch, or Yki using the wing-specific driver does not result in the outstretched wing. Furthermore, our data indicate that genetic alterations associated with the spread-out wing phenotype originate in enteroblasts (EBs) during early development. RNA sequencing analysis with guts from third instar larvae revealed that the JAK-STAT pathway ligand Upd2 is among the most significantly downregulated transcripts. Notably, ectopic expression of Upd2 in EBs partially rescued the abnormal held-out wing phenotype induced by TDP-43, Notch, and Yki overexpression. Together, our findings identify gut-derived Upd2 cytokine signaling as a key mediator of the outstretched wing phenotype, providing evidence for gut-to-wing communication axis during Drosophila development.