Integrated Genetic Networks and Epigenetic Regulation inTooth Development and Maturation

Tooth development or odontogenesis is a complex morphogenetic process that requires tightly regulated interactions between the oral epithelium and mesenchyme of neural crest origin. In this narrative review, we compile existing knowledge regarding gene regulatory networks and epigenetic factors throughout tooth development from initiation to eruption. Signaling between the epithelium and mesenchyme is mediated by four conserved pathways-Wnt/β-catenin, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Sonic hedgehog (Shh)-which operate iteratively and interact through extensive crosstalk at each developmental stage. Transcription factors, such as PAX9, MSX1, PITX2, and LEF1, interpret these signals to control cell fate decisions and differentiation. Epigenetic modifications, including DNA methylation, histone modifications, and microRNA-mediated regulation, provide additional layers of control that fine-tune gene expression programs. Unlike existing reviews that address these regulatory mechanisms separately, here we integrate signaling pathways, transcription factor networks, epigenetic regulation, human genetic disorders, dental stem cell biology, and recent single-cell transcriptomic insights into a unified framework. We discuss opportunities to apply developmental biology knowledge towards regenerative dentistry goals, including iPSC-derived dental models and spatially resolved multi-omics approaches, while acknowledging the considerable gap between preclinical findings and clinical applications.