Retinoic-acid modulation of epithelial bioelectric networks supports sequential and complementary roles for quiescent and growth phases in pattern-memory consolidation

Across regeneration-competent vertebrates, appendage regrowth unfolds in repeating cycles of quiescence (Q) followed by growth (G). Yet the respective functions of these phases, and the origin of their stereotypic alternation, remain poorly understood. Using a simplified biophysical morphogenesis model, we examined how fluctuations in retinoic-acid (RA) tone, acting via nuclear RARs, sculpt tissue-level dynamics and pattern memory. We demonstrate that the low and high RA titres characteristic of Q and G phases, respectively, are likely to serve critical, sequential roles in consolidating positional information. The tissue behaviours that underlie these roles emerge from RA-driven shifts in cell membrane voltage and in the balance between activator and suppressor signals across the regenerating field. Under low RA, diminished recruitment of suppressor fibroblasts results in tissue-wide disinhibition: bursts of synchronized depolarization initiated by positional-memory cells drive enlistment of additional progenitors into the blastema. Conversely, elevated RA amplifies suppressor activity, restricting bioelectrical excitability to only the most strongly specified progenitors, thereby pruning the expanded blastema and sharpening positional cues. Taken together, these findings offer a testable framework for how phase-specific RA modulation can coordinate the iterative recruitment and refinement steps required for robust pattern-memory consolidation during vertebrate appendage regeneration.