A spreading, multi-tissue wound signal initiates whole-body regeneration

ABSTRACTAnimal bodies are equipped to sense injuries and respond, and rapid activation of ERK signaling at wound sites has emerged as a recurring mechanism across metazoans. During whole-body regeneration, distant species including cnidarians, planarians and echinoderms activate ERK at wounds to drive early transcriptional changes. However, it is unclear to what extent these are distinct phenomena, utilizing a common effector pathway but with different upstream inputs and downstream functions, or are more deeply alike, sharing upstream inputs, activating cell type(s), or spatiotemporal dynamics. To facilitate thorough comparisons across animals, we examined wound-induced ERK during whole-body regeneration in the acoel Hofstenia miamia. ERK signaling is induced at wound sites within 10 minutes post-amputation and peaks in activity within one hour. ERK is required for head and tail regeneration and inhibiting ERK suppresses the expression of wound-induced genes, which are themselves required for regeneration. Quantification of spatial dynamics revealed that active ERK spreads rapidly away from the wound site during the first 30 minutes post-amputation and continues to expand in space through 3-6 hours, albeit at lower levels. Multiple cell types activate ERK including neoblasts (stem cells) and muscle, and ERK is spatially dynamic within both cell types, however, ERK activation in muscle does not require neoblasts. Finally, neuregulin-1, a putative ligand produced exclusively by muscle cells, is required for ERK activation at wounds. Altogether, our data identify a key signaling role of muscle cells in driving ERK activation in multiple cell types after injury, and describe a spatial spreading phenomenon with parallels to dynamic ERK patterns in other systems.