The enamel knot as a signaling center in the developing mouse tooth.

Mammalian tooth forms are produced during development by folding of the enamel epithelium but the molecular mechanisms involved in the formation and patterning of tooth cusps are not understood. We now report that several key signaling molecules found in well-known vertebrate signaling tissues such as the node, the notochord, the apical ectodermal ridge, and the zone of polarizing activity in the limb bud are specifically expressed in cells of the enamel knot, which is a transient cluster of dental epithelial cells. By comparing three-dimensional reconstructions of serial sections following in situ hybridization we localized Sonic hedgehog, Bone morphogenetic proteins-2, -4 and -7, as well as Fibroblast growth factor-4 in nested domains within the enamel knot. We suggest that the enamel knot acts as a signaling or organizing center, which provides positional information for tooth morphogenesis and regulates the growth of tooth cusps.