During Drosophila disc regeneration, JAK/STAT coordinates cell proliferation with Dilp8-mediated developmental delay

Significance The larval imaginal discs of the fruit fly are capable of fully regenerating mechanically damaged parts. Wound healing is initiated by the JNK signaling pathway. We followed the subsequent formation of the regenerating blastema by transcriptome profiling and identified the JAK/STAT pathway as a central regulatory node controlling local cellular and global physiological responses. This signaling cascade induces, together with the Wingless pathway, proliferation of cells forming the blastema. However, JAK/STAT also up-regulates Drosophila insulin-like peptide 8 (Dilp8), a paracrine factor involved in organismal developmental delay, thereby allowing regenerative recovery. Regeneration of fragmented Drosophila imaginal discs occurs in an epimorphic manner involving local cell proliferation at the wound site. After disc fragmentation, cells at the wound site activate a restoration program through wound healing, regenerative cell proliferation, and repatterning of the tissue. However, the interplay of signaling cascades driving these early reprogramming steps is not well-understood. Here, we profiled the transcriptome of regenerating cells in the early phase within 24 h after wounding. We found that JAK/STAT signaling becomes activated at the wound site and promotes regenerative cell proliferation in cooperation with Wingless (Wg) signaling. In addition, we showed that the expression of Drosophila insulin-like peptide 8 ( dilp8 ), which encodes a paracrine peptide to delay the onset of pupariation, is controlled by JAK/STAT signaling in early regenerating discs. Our findings suggest that JAK/STAT signaling plays a pivotal role in coordinating regenerative disc growth with organismal developmental timing.