Melanization regulates wound healing by limiting polyploid cell growth in the Drosophila epithelium post injury

Wound healing requires a localized response that restricts growth, remodeling, and inflammation to the site of injury. In the fruit fly, Drosophila melanogaster, the epithelium heals puncture wounds through cell growth instead of cell division. Epithelial cells on wound margin both fuse and duplicate their genome to generate a multinucleated, polyploid cell essential for tissue repair. Despite the essential role of polyploidy in wound healing, the signals that initiate and regulate the extent of cell growth at the wound site remain poorly understood. One of the first steps in wound healing requires the deposit of melanin at the site of injury, which persists as a melanin scar. The melanin scar forms within hours after a puncture wound and is dependent on the activation of three prophenoloxidase genes (PPO1, PPO2, and PPO3). Using a triple loss of function mutant (PPOnull), we have uncovered a novel role for melanization in regulating wound healing by limiting polyploid cell growth post injury. Thus, melanization is required for efficient wound closure and its loss leads to an unexpected exacerbation of polyploid cell growth in the surrounding epithelial cells. This occurs, in part, through the early entry of epithelial cells into the endocycle, which may be due to altered gene expression as a result of delayed JNK signaling and other pathways. In conclusion, we have found that polyploid cell growth requires melanization at the injury site to control the extent of cell growth and regulate wound repair. SUMMARYPuncture wounds in insects are known to lead to production of a pigmented (melanin) deposit that can persist as a scar, remodeling the site of damage. It has long been speculated that the melanin scar is necessary for tissue repair, thus we used the fruit fly as a model to determine how loss of scar formation affects wound healing. In doing so, we discovered that the melanin scar is necessary to restrict cell growth and facilitate efficient wound closure. Thus, revealing a pivotal role for scar formation in coordinating cell growth, which may be conserved in other organisms.