Affiliations: 1) Hilde Mangold Haus, University of Freiburg; 2) Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg; 3) Institute of Physics, University of Freiburg; 4) CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg; 5) BIOSS Centre for Biological Signalling Studies, University of Freiburg
Keywords: k. regeneration; e. JAK/STAT
Epithelia are frequently exposed to extracellular insults and damage due to their exposed position. The restoration of homeostasis upon damage relies on regulated activation of complex stress-responsive signaling pathways to coordinate cellular responses such as apoptosis, G2 stalling, proliferation and survival. Consequently, deviations from these coordinated responses, due to prolonged or potent damage, lie at the center of chronic wound pathologies. Despite their importance, the understanding of how spatial patterns of signaling pathways guide repair behaviors, how the extent of damage is matched by a response of appropriate duration and strength, and how precisely these processes become deviated within damaged tissues remains elusive. Using TNF-α/Eiger-mediated damage to the wing imaginal disc of Drosophila, we observe a stratification of cellular responses coinciding with the spatial patterns of the JNK and JAK/STAT pathways. We find a distinct cell-autonomous repression of JAK/STAT by JNK, and demonstrate through mathematical modeling the importance of such repression to generate our observed spatial patterns. Importantly, JNK-dependent G2 stalling is overridden by ectopic expression of JAK/STAT, leading to increased apoptosis in the tissue. This suggests that the repression of JAK/STAT by JNK is essential to stratify distinct cellular repair behaviors at the wound site. Understanding how perturbations to these patterns impair regenerative responses would be a step towards creating new perspectives into previously uncharacterized links between important signaling pathways and their underlying repair behaviors - which fundamentally influence wound healing pathologies.