MyD88-JNK/p38-APP axis: An innate immunity-hormone bridge governs irreversible metamorphic fate in the sea star, Patiria pectinifera

How organisms translate external environmental cues into irreversible internal developmental programs remains a fundamental question in biology. Using the sea star, Patiria pectinifera, which transforms in response to microbial biofilm, we deployed transcriptomics, dynamic network analysis, and pharmacological rescue assays to dissect this transition. We identified a three-tiered signaling cascade initiated by MyD88-dependent innate immunity. Crucially, this immune signal is functionally converted by JNK/p38 MAPK activity into a retinoic acid hormonal commitment signal. This commitment signal then converges on the Amyloid Precursor Protein (APP), positioned as the irrevocable commitment gateway, to execute the irreversible metamorphic switch. Downstream of APP, the signal orchestrates a neuro-developmental program, predicted to be TFAP2A-mediated, governing adult nervous system reconstruction. Our findings resolve the missing link between external stimuli and developmental fate, establishing APP's ancient, non-pathological function as a universal Environmental-Developmental signal converter and offering an evolutionary framework for understanding the conserved interplay between immunity and neural development.