Molecular patterning of the mammalian dentition

• Integrated networks of Bmp, Fgf, Shh, and Wnt pathways regulate tooth organogenesis.
• Increased activity of Fgf, Shh, or Wnt signaling revitalizes mouse vestigial teeth.
• Bmp4–Msx1 positive feedback loop drives expansion of tooth developmental field.
• Osr2 patterns odontogenic mesenchyme along buccolingual and anteroposterior axes.
• The Wnt–Shh and Bmp–Sostdc1 negative feedback loops regulate spatial tooth patterning.

Four conserved signaling pathways, including the bone morphogenetic proteins (Bmp), fibroblast growth factors (Fgf), sonic hedgehog (Shh), and wingless-related (Wnt) pathways, are each repeatedly used throughout tooth development. Inactivation of any of these resulted in early tooth developmental arrest in mice. The mutations identified thus far in human patients with tooth agenesis also affect these pathways. Recent studies show that these signaling pathways interact through positive and negative feedback loops to regulate not only morphogenesis of individual teeth but also tooth number, shape, and spatial pattern. Increased activity of each of the Fgf, Shh, and canonical Wnt signaling pathways revitalizes development of the physiologically arrested mouse diastemal tooth germs whereas constitutive activation of canonical Wnt signaling in the dental epithelium is able to induce supernumerary tooth formation even in the absence of Msx1 and Pax9, two transcription factors required for normal tooth development beyond the early bud stage. Bmp4 and Msx1 act in a positive feedback loop to drive sequential tooth formation whereas the Osr2 transcription factor restricts Msx1-mediated expansion of the mesenchymal odontogenic field along both the buccolingual and anteroposterior axes to pattern mouse molar teeth in a single row. Moreover, the ectodermal-specific ectodysplasin (EDA) signaling pathway controls tooth number and tooth shape through regulation of Fgf20 expression in the dental epithelium, whereas Shh suppresses Wnt signaling through a negative feedback loop to regulate spatial patterning of teeth. In this article, we attempt to integrate these exciting findings in the understanding of the molecular networks regulating tooth development and patterning.