Scheme of tooth development. Tooth development begins with the evagination of the epithelium into the underling mesenchyme to form the tooth bud. During crown formation, enamel knots serve as the signaling center to mediate the differentiation of odontoblasts and ameloblasts, and the patterning of the cusps. Starting from postnastal day 3.5, bilayered HERS grows apically and guides the tooth root development. HERS, Hertwig’s epithelial root sheath; AP, apical papilla; FUR, furcation.