JNK signalling balances apoptosis and cell survival during tissue stress

Recovery from tissue stress requires the elimination of damaged cells and the commensurate production of healthy cells. How these two processes are coordinated to ensure tissue recovery remains poorly understood. Here we show that the c-Jun N-terminal kinase (JNK) pathway orchestrates apoptosis and proliferation, two seemingly opposite cellular behaviours, in response to epithelial stress. We took advantage of new optogenetic tools to trigger a pulse of JNK signalling activity in a defined domain of Drosophila wing primordia and mapped the response in time and space. Within 3 h after induction, the cells within the activation domain arrest proliferation, while a subset undergo apoptosis. As JNK signalling returns to background level, apoptosis subsides and proliferation resumes to allow completion of development with high fidelity. Using a sensitive reporter, we find that while JNK triggers apoptosis, the level of JNK activity does not correlate with apoptosis on a cell-by-cell basis. We show that the cell cycle phase modulates the pro-apoptotic activity of JNK signalling: G2 arrest is protective, while, in G1, mild JNK signalling activity suffices to trigger apoptosis. Transcriptomic analysis identified the genes encoding Dally and Dally-like protein (Dlp) among the most upregulated by excess JNK signalling. We show that these glypicans contribute to tissue repair by enhancing surface retention of the ligands Wingless (a Wnt) and Dpp (a BMP). We suggest that the resulting local increase in morphogen signalling provides subsequent protection from the pro-apoptotic effect of JNK signalling, allowing surviving cells to re-enter the cell cycle and resume development. Accordingly, recovery from ribosomal protein deficiency or irradiation-induced stress is impaired upon reduction of Dlp activity. Our work shows how a single stress pathway can selectively trigger apoptosis while protecting cells that can contribute to tissue recovery during resumption of normal development.