A p63-dependent molecular switch directs epithelial fate to form a specialized seal at the tooth-gingiva interface

Failure to maintain the epithelial seal at the tooth-gingiva interface drives periodontitis. This specialized junctional epithelium (JE) is critical for immune homeostasis, yet mechanisms for its regeneration are poorly understood. Using murine gingivectomy, single-cell transcriptomics, lineage tracing, and clinical data, we delineate requirements for JE repair. We identify ODAM as a specific JE marker derived from Krt5+ basal progenitors. We show these cells migrate from distal sites, explaining the superior outcomes of progenitor-preserving single flap surgery. Genetic deletion of p63 blocks JE regeneration and disrupts cellular organization. We define an essential p63-RUNX1-ODAM axis for JE specification, distinct from the p63-KLF4-loricrin pathway driving keratinization-a feature of pathological repair. These findings reveal a fundamental molecular switch controlling epithelial fate, offering a roadmap to therapeutically promote tissue sealing at inflammation-prone interfaces.