ISL1 regulates the differentiation and maintenance of dental epithelial stem cells in the incisor

Enamel is asymmetrically distributed in mouse incisors, which grow throughout life, and this continuous renewal is driven by dental epithelial stem cells (DESCs). In this study, we report that ablation of Isl1 in the dental epithelium using Pitx2‐Cre leads to impaired development of the mandibular incisors. In Isl1 Pitx2Cre mutant embryos, the mandibular incisors exhibited a significant reduction in size and length compared to wild‐type controls. A significant decrease in the proliferation of epithelial and mesenchymal cells was also detected in Isl1 Pitx2Cre mutant incisors, and cell apoptosis was markedly increased in the lateral cervical loop of Isl1 Pitx2Cre mutant incisors at E17.5. Ameloblasts and enamel were present on all surfaces of the mandibular incisor, including the labial side. Transcriptome analysis and in situ hybridisation revealed that Isl1 deletion induced significant upregulation of Hedgehog pathway components ( Shh , Ptch1 , Gli1 ) and FGF signalling mediators ( Fgf3 , Etv4 , Etv5 ), while downregulating dental epithelial stem cell markers Sox2 and Lgr5 . Our results showed that ISL1 co‐localised with SOX2 in the lingual and lateral dental epithelium of mandibular incisors, and the expression of Sox2 was regulated by Isl1 . Our results demonstrate that Isl1 sustains DESC viability and orchestrates ameloblast lineage commitment via SOX2‐mediated regulation during incisor morphogenesis.