title: Epiprofin Regulates Enamel Formation and Tooth Morphogenesis by Controlling Epithelial-Mesenchymal Interactions During Tooth Development.
abstract: The synchronization of cell proliferation and cytodifferentiation between dental epithelial and mesenchymal cells is required for the morphogenesis of teeth with the correct functional shapes and optimum sizes. Epiprofin (Epfn), a transcription factor belonging to the Sp family, regulates dental epithelial cell proliferation and is essential for ameloblast and odontoblast differentiation. Epfn deficiency results in the lack of enamel and ironically the formation of extra teeth. We investigated the mechanism underlying the functions of Epfn in tooth development through the creation of transgenic mice expressing Epfn under the control of an epithelial cell-specific K5 promoter (K5-Epfn). We found that these K5-Epfn mice developed abnormally shaped incisors and molars and formed fewer molars in the mandible. Remarkably, ameloblasts differentiated ectopically and enamel was formed on the lingual side of the K5-Epfn incisors. By contrast, ameloblasts and enamel were found only on the labial side in wild-type mice, as Follistatin (Fst) expressed in the lingual side inhibits BMP4 signaling necessary for ameloblast differentiation. We showed that Epfn transfection into the dental epithelial cell line SF2 abrogated the inhibitory activity of Fst and promoted ameloblast differentiation of SF2 cells. We found that Epfn induced FGF9 in dental epithelial cells and this dental epithelial cell-derived FGF9 promoted dental mesenchymal cell proliferation via the FGF receptor 1c (FGFR1c). Taken together, these results suggest that Epfn preserves the balance between cell proliferation and cytodifferentiation in dental epithelial and mesenchymal cells during normal tooth development and morphogenesis. © 2016 American Society for Bone and Mineral Research.
authors: Division of Molecular Pharmacology and Cell Biophysics, Department of Oral Biology, Tohoku University Graduate School of Dentistry, Sendai, Japan.|Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors: Takashi
authors: T
authors: Nakamura
authors: Institute of Oral Biology, Center of Dental Medicine, University of Zurich, Zurich, Switzerland.
authors: Lucia
authors: L
authors: Jimenez-Rojo
authors: Division of Orthopedic Research Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Eiki
authors: E
authors: Koyama
authors: Division of Orthopedic Research Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Maurizio
authors: M
authors: Pacifici
authors: Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo, Japan.
authors: Susana
authors: S
authors: de Vega
authors: Division of Orthopedic Research Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Masahiro
authors: M
authors: Iwamoto
authors: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai, Japan.
authors: Satoshi
authors: S
authors: Fukumoto
authors: Department of Cell Biology and Histology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors: Fernando
authors: F
authors: Unda
authors: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors: Yoshihiko
authors: Y
authors: Yamada
mesh_terms: D000565:Ameloblasts / Q000378:metabolism; D000566:Amelogenesis; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D003743:Dental Enamel / Q000254:growth & development / Q000378:metabolism*; D003771:Dental Papilla / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D051525:Fibroblast Growth Factor 9 / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D007180:Incisor / Q000254:growth & development / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism*; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008954:Models, Biological; D008963:Molar / Q000254:growth & development / Q000378:metabolism; D009805:Odontogenesis; D019228:Tooth Crown / Q000254:growth & development / Q000378:metabolism
chemical_list: D015415:Biomarkers; C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C465570:Shh protein, mouse; C498818:Sp6 protein, mouse
keywords: AMELOBLAST; EPIPROFIN; FGF9; ODONTOBLAST; TOOTH DEVELOPMENT