Smad-dependent and -independent MAPK pathways in mediating tooth development

BMP signaling plays crucial roles in regulating tooth development. The basic BMP signaling engine consists of a receptor complex that activates Smads and a Smad-containing complex that controls transcription of the downstream target genes. To date, studies show that Smad4 serves as the central intracellular effector of BMP signaling. Smad4 binds with receptor activated Smads and forms a complex, which then moves into the nucleus to regulate downstream target genes. Besides Smad-mediated transcription, BMP signaling activates other signaling cascades, including p38 MAPK pathways. Objective: To investigate the biological function of Smad4-dependent and -independent p38 MAP kinase pathways during tooth development. Methods: We generated epithelial specific Smad4 mutant mice and cultured the tooth germ. Results: Ablation of Smad4 in the dental epithelium does not block early tooth development and only causes dental cusp patterning defect and blocks root development. When we block p38 MAPK signaling in the Smad4 mutant, tooth development is arrested at the bud stage. Conclusion: These results provide definitive evidence that BMP signal is mediated through both Smad4-dependent and -independent manner. Both cascades are required for tooth development. Supported by R01 DE012711 and R01 DE014078, NIDCR, NIH.