An ARID3A-dependent progenitor lineage confers developmental robustness to palate morphogenesis

Abstract The periderm prevents pathological adhesions during orofacial development, yet its lineage origins remain unresolved. Here, we define the murine palatal epithelial hierarchy, identifying a transient, ARID3A-defined K5+;K14– progenitor subpopulation programmed for periderm differentiation. Genetic ablation of Arid3a impairs this lineage, causing severe delay in palate closure rather than complete failure. This "delayed-but-functional" phenotype reveals a mechanism of developmental robustness, wherein ARID3A drives a rapid lineage trajectory essential for timely morphogenesis. Mechanistically, ARID3A binds a distal enhancer to activate the key periderm regulator Grhl2. Furthermore, integrating our multi-omic atlas with human genetics demonstrates that enhancers in this ARID3A-dependent lineage are enriched for risk variants associated with orofacial clefts. Our findings identify a specific progenitor lineage that confers developmental robustness and provides a cellular address for human genetic risk.