Activin and Bmp4 Signaling Converge on Wnt Activation during Odontogenesis.
Previous studies show that both activin and Bmp4 act as crucial mesenchymal odontogenic signals during early tooth development. Remarkably, mice lacking activin-βA ( Inhba-/-) and mice with neural crest-specific inactivation of Bmp4 ( Bmp4ncko/ncko) both exhibit bud-stage developmental arrest of the mandibular molar tooth germs while their maxillary molar tooth germs completed morphogenesis. In this study, we found that, whereas expression of Inhba and Bmp4 in the developing tooth mesenchyme is independent of each other, Bmp4ncko/nckoInhba-/- compound mutant mice exhibit early developmental arrest of all tooth germs. Moreover, genetic inactivation of Osr2, a negative regulator of the odontogenic function of the Bmp4-Msx1 signaling pathway, rescues mandibular molar morphogenesis in Inhba-/- embryos. We recently reported that Osr2 and the Bmp4-Msx1 pathway control the bud-to-cap transition of tooth morphogenesis through antagonistic regulation of expression of secreted Wnt antagonists, including Dkk2 and Sfrp2, in the developing tooth mesenchyme. We show here that expression of Dkk2 messenger RNAs was significantly upregulated and expanded into the tooth bud mesenchyme in Inhba-/- embryos in comparison with wild-type littermates. Furthermore, in utero treatment with either lithium chloride, an agonist of canonical Wnt signaling, or the DKK inhibitor IIIC3a rescued mandibular molar tooth morphogenesis in Inhba-/- embryos. Together with our finding that the developing mandibular molar tooth bud mesenchyme expresses significantly higher levels of Dkk2 than the developing maxillary molar tooth mesenchyme, these data indicate that Bmp4 and activin signaling pathways converge on activation of the Wnt signaling pathway to promote tooth morphogenesis through the bud-to-cap transition and that the differential effects of loss of activin or Bmp4 signaling on maxillary and mandibular molar tooth morphogenesis are mainly due to the differential expression of Wnt antagonists, particularly Dkk2, in the maxillary and mandibular tooth mesenchyme.
['Kwon|H-J E|HE|', 'Jia|S|S|', 'Lan|Y|Y|', 'Liu|H|H|', 'Jiang|R|R|']
D028341:Activins D000818:Animals D055415:Bone Morphogenetic Protein 4 D018507:Gene Expression Regulation, Developmental D017403:In Situ Hybridization D036341:Intercellular Signaling Peptides and Proteins D061346:Laser Capture Microdissection D018021:Lithium Chloride D008565:Membrane Proteins D051379:Mice D008822:Mice, Transgenic D008963:Molar D009805:Odontogenesis D012333:RNA, Messenger D060888:Real-Time Polymerase Chain Reaction D015398:Signal Transduction D014083:Tooth Germ D014157:Transcription Factors D060449:Wnt Signaling Pathway
tooth development morphogenesis genetics cell signaling growth factors hypodontia