Redox-modulated ERK dynamics support wound-dependent tissue formation during early planarian regeneration

The mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) pathway is essential during regeneration as it guides stem cell proliferation, differentiation, and survival. We identified redox-dependent components of MAPK-ERK signaling whose coordinated activity is required for full-body regeneration and patterning. Wound orientation was found to influence ERK activation and redox dynamics, with anterior-facing wounds showing elevated ERK activity 3-6 h post-amputation, together with increased superoxide and hydrogen peroxide levels, compared to posterior-facing wounds. Disruption of MAPK signaling produced distinct effects on anterior versus posterior regeneration that depended on both wound orientation and the fragment's original anterior-posterior identity. In fragments containing anterior- and posterior-facing wounds, this molecular gradient was re-established within 6 h. Additionally, our findings suggest a feedback regulatory circuit controlling ERK activation, in which the transcription factor egr-4 (early growth response protein 4) inhibits MAPK phosphatase activity. In summary, amputation-induced redox signals coordinate with the MAPK-ERK-egr4 signaling pathway to ensure correct regeneration and tissue patterning in planarians.