Divergent paracrine dynamics originate parallel morphogenetic programs during appendage regeneration

To enable diverse pattern formation and growth, regenerating tissues deploy divergent cell–cell interactions to establish parallel morphogenetic programs. Yet, connecting subcellular secretory rules to tissue-level segregation of patterning remains difficult. Here we examine how parallel programs arise in the zebrafish caudal fin, where individual wound-epidermal signaling hubs (WESHs) broadcast cues to numerous blastema cell cohorts (BCs). We compared the impact of a single WESH’s secretion on two distinct BC lineages. One lineage exhibited sustained mitogenic responses to Sonic hedgehog that scaled divisively with stimulus intensity; the other produced transient responses that adapted subtractively. The contrasting signal-coding dynamics originated from differences in the kinetics of WESH secretory microdomains that contact each BC type. Sustained BC activity depended on microdomains that recovered vesicle content rapidly enough to maintain continuous ligand release. Divisive adaptation arose from a slow, cell-intrinsic gain control mediated by the Na+/K+-ATPase, which progressively hyperpolarized the receiving BCs. Transient BC activity stemmed from microdomains that refilled too slowly to sustain prolonged secretion but that transiently potentiated when WESH calcium influx increased. Disrupting this potentiation with the fast calcium chelator EGTA, or attenuating the vesicle-priming factor Munc13b, reduced the initial transient burst. Subtractive adaptation was imposed by the nonlinear threshold required for downstream transcription factor activation in the BCs. In vivo lineage tracing revealed that transient BCs drive a brief surge in outgrowth velocity, whereas sustained BCs exert prolonged yet finely graded influence on fin shape. Thus, subcellular secretory specialization offers a compact and efficient mechanism for generating parallel information streams that orchestrate specialized phases of regeneration.