Odontogenesis, the intricate process of tooth development, involves complex interactions between oral ectoderm epithelial cells and ectomesenchymal cells derived from the cephalic neural crest, regulated by major signaling pathways. Dental developmental anomalies provide valuable insights for clinical diagnosis of rare diseases. More than 30% of rare diseases patients who undergo molecular analysis suffer from diagnostic errancy. In the search for up-to-date technologies and methods to study the pathophysiology of new candidate genetic variants, causing tooth mineralized tissues anomalies, we have developed an original model of tooth organoids with human or mouse cell lines of ameloblast-like cells and odontoblasts derived from the pulp. This in vitro 3D cellular model reproducing the two main compartments of the bell stage of tooth development between ameloblasts and odontoblasts, specific to enamel and dentin morphogenesis, respectively, mimics the epithelio-mesenchymal interactions during the dental bell stage of tooth morphogenesis and will facilitate the study of enamel and dentin genetic anomalies, allowing the functional validation of newly identified mutations (variants of uncertain significance -VUS- or new candidate genes).