Fig. 1

Mouse lower and upper first molars and their development. a Top: Lateral view of the mouse upper first molar showing its cusps. Bottom: Crown views of mouse lower and upper first molars. Drawings after [99]. b Simplified view of the tooth germ, composed of three main tissues: mesenchyme, epithelium, and (epithelial) enamel knot (EK), which serves as an epicenter for epithelium differentiation. c Scheme summarizing the main steps of molar development. At ED10.5, the lower and upper molars presumptive fields are specified in regionalized first branchial arch. At this point, the development of the molar rows is starting. By ED13.5, the first molars reach the bud stage: the oral epithelium has invaginated and tops a condensing mesenchyme of neural crest origin. Epithelium–mesenchyme interactions then lead to the formation of a signaling center in the invaginated oral epithelium, called the primary enamel knot (PEK), whose origin can be complex [100, 101]. The PEK directs the growth of dental epithelium around the further condensing and rapidly growing dental mesenchyme (bud-cap transition), resulting in the cap stage. This marks the beginning of the morphogenesis of the molar crown. Next, secondary enamel knots (SEK) are patterned sequentially. They sit at the tip of the future cusps and drive their morphogenesis, resulting in the bell stage. SEK patterning in lower molars is schematized with a domino and the period of SEK patterning in lower (black bar) versus upper molars (orange bar) is shown. SEK also act as epicenters for the progression of proliferation arrest and differentiation. Epithelial and mesenchymal cells situated at the inner interface between these two compartments differentiate into ameloblasts and odontoblasts, respectively, and at the very end of fetal life, those cells will start producing enamel and dentin, respectively. Note that the successive steps start sequentially but largely overlap because the downgrowth of the epithelium continues while cusps are patterned and the differentiation of the first cusps starts before the last cusps are formed