Alternative Mediator for TGF-β/BMP Signaling During Tooth and Palate Development

TGF-β/BMP signaling plays a crucial role in an array of biological processes, including embryonic patterning, organogenesis, wound healing, and carcinogenesis. Previous studies have indicated that Smad4 serves as the central intracellular effector of TGF-β signaling. In this study, we found that p38 MAPK is specifically activated by TGF-β and functions as a complementary effector in mediating Smad4-independent TGF-β signaling during craniofacial organogenesis. Objective: To investigate the biological function of Smad4-dependent and –independent p38 MAPK pathways during tooth and palate development. Methods: We specifically inactivate Smad4 in both dental and palatal epithelium by using the Cre/loxp system in vivo, and block p38 MAPK signaling in an organ culture system by siRNA or p38 MAPK inhibitor. Results: Unlike the Bmpr1a mutant, ablation of Smad4 in the dental epithelium does not block early tooth development and only causes defects in dental cusp patterning and root development. Inactivation of p38 MAPK signaling in the Smad4 mutant results in the arrest of tooth development at the bud stage, a phenotype identical to that of Bmpr1a mutant mice. Similarly, ablation of Smad4 in the palatal epithelium does not cause cleft palate, but blocking p38 MAPK and Smad4 together does, reproducing the phenotype of Tgfbr2 mutant mice. Conclusion: Our study demonstrates that p38 MAPK mediated Smad4-independent TGF-β signaling is a widely used mechanism in regulating embryonic organogenesis. Supported by R01 DE012711 and R01 DE014078, NIDCR, NIH.