Acoel whole-body regeneration begins with spreading, multi-tissue ERK signaling downstream of neuregulin-1

Rapid activation of ERK (extracellular signal-regulated kinase) signaling drives transcriptional responses to injury across metazoans. Yet, it is unclear whether key aspects of ERK as a wound signal—its upstream inputs, activating cell type(s), and spatiotemporal pattern—are conserved. To facilitate thorough comparisons, we examined wound-induced ERK during whole-body regeneration in the acoel Hofstenia miamia . Wounding triggers rapid ERK activation, which begins in the most wound-proximal cells but expands distally over time among stem cells and muscle cells. ERK drives transcriptional responses to wounding in both cell types, and inhibiting ERK activation perturbs the progress of regeneration. Finally, neuregulin-1 , a ligand produced exclusively by muscle cells, and its putative receptor egfr-1 (epidermal growth factor receptor-1) act upstream of ERK activation upon wounding. Our data identify a key signaling role of muscle cells in driving ERK activation following injury and reveal a spatial spreading phenomenon with both parallels to and distinctions from dynamic ERK patterns in other systems.