A Protease-initiated Model of Wound Detection
O'Connor, James Thomas
0000-0003-2642-1594
:
2022-02-16
Abstract
When an organism is injured, the damaged tissue recognizes the presence and severity of the wound and rapidly responds to repair the injury and restore proper tissue functionality. But how do cells first detect the presence of a wound? In epithelial cells, the earliest known wound response, occurring within seconds, is a dramatic increase in cytosolic calcium. After wounding in Drosophila pupae, two mechanistically distinct calcium responses are observed. Extracellular calcium rushes into damaged cells within seconds, before diffusing the neighboring cells through gap junctions. Then, about one minute after wounding, distal cells far from the wound begin to have an increase in cytosolic calcium through an independent mechanism. This dissertation presents evidence that wounds in Drosophila epithelia trigger a cytosolic calcium increase by activating extracellular cytokines, Growth-blocking peptides (Gbps), which initiate signaling in surrounding epithelial cells through the G-protein coupled receptor, Methuselah-like 10 (Mthl10). Latent Gbps are present in unwounded tissue and are activated by proteolytic cleavage. Further, multiple different protease families can activate Gbps in imaginal wing discs suggesting Gbps act as a generalized protease-detector system. In this way, this project has characterized a protease-initiated wound detection system, whereby proteases released during wound-induced cell lysis serve as the instructive signal, activating Gbp ligands, which bind to Mthl10 receptors on epithelial cells distal from the wound to elicit an increase in cytosolic calcium that initiates cellular wound responses.