title: p38α MAPK is required for tooth morphogenesis and enamel secretion.
abstract: 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 p38α MAPK in ectodermal appendages using K14-cre mice (p38α(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 p38α, expression of amelogenin and β4-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 p38α in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38α functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38α MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel.
authors.affiliation: From the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, mag3003@med.cornell.edu.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Greenblatt
authors.affiliation: the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Hwanhee
authors.initials: H
authors.lastname: Oh
authors.affiliation: the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, the Department of Microbiology, Brain Korea 21 PLUS Project for Medical Sciences and Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kwang Hwan
authors.initials: KH
authors.lastname: Park
authors.affiliation: the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Choo
authors.affiliation: the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Sano
authors.affiliation: the Department of Biochemistry, University of Vermont College of Medicine, Burlington, Vermont, 05405.
authors.forename: Coralee E
authors.initials: CE
authors.lastname: Tye
authors.affiliation: the Forsyth Institute, Cambridge, Massachusetts 02142.
authors.forename: Ziedonis
authors.initials: Z
authors.lastname: Skobe
authors.affiliation: the Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
authors.affiliation: the Department of Surgery, Massachusetts General Hospital, Shriners Burns Hospital, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Marianna
authors.initials: M
authors.lastname: Bei
authors.affiliation: the Department of Medicine, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.affiliation: the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, jas2060@med.cornell.edu.
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Shim
mesh_terms: D000565:Ameloblasts / Q000166:cytology / Q000378:metabolism*; D053523:Amelogenin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D003743:Dental Enamel / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007180:Incisor / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D009805:Odontogenesis / Q000235:genetics*; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D053523:Amelogenin; C507200:Amelx protein, mouse; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D039663:Integrin beta4; C525820:bmp7 protein, mouse; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D048308:Mitogen-Activated Protein Kinase 14; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse
keywords: Ameloblast; Bone Morphogenetic Protein (BMP); Ectodermal Dysplasia; Microtubule-associated Protein (MAP); SMAD Transcription Factor; Tooth Development; p38 MAPK