p38alpha MAPK is required for tooth morphogenesis and enamel secretion

UMMS Affiliation

Program in Molecular Medicine

Publication Date


Document Type



Ameloblasts; Amelogenin; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Cell Differentiation; Cell Proliferation; Dental Enamel; *Gene Expression Regulation, Developmental; Incisor; Integrin beta4; MAP Kinase Kinase 3; MAP Kinase Kinase 6; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 14; Odontogenesis; Signal Transduction; Tissue Culture Techniques; p21-Activated Kinases


Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology


An improved understanding of the molecular pathways that drive tooth morphogenesis and enamel secretion is needed to generate teeth from organ cultures for therapeutic implantation or to determine the pathogenesis of primary disorders of dentition (Abdollah, S., Macias-Silva, M., Tsukazaki, T., Hayashi, H., Attisano, L., and Wrana, J. L. (1997) J. Biol. Chem. 272, 27678-27685). Here we present a novel ectodermal dysplasia phenotype associated with conditional deletion of p38alpha MAPK in ectodermal appendages using K14-cre mice (p38alpha(K14) mice). These mice display impaired patterning of dental cusps and a profound defect in the production and biomechanical strength of dental enamel because of defects in ameloblast differentiation and activity. In the absence of p38alpha, expression of amelogenin and beta4-integrin in ameloblasts and p21 in the enamel knot was significantly reduced. Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase of p38alpha in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38alpha functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38alpha MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel.


Ameloblast, Bone Morphogenetic Protein (BMP), Ectodermal Dysplasia, Microtubule-associated Protein (MAP), SMAD Transcription Factor, Tooth Development, p38 MAPK

DOI of Published Version



J Biol Chem. 2015 Jan 2;290(1):284-95. doi: 10.1074/jbc.M114.599274. Epub 2014 Nov 18. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of biological chemistry

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