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J Bone Miner Res. 2017 Mar;32(3):601-610. doi: 10.1002/jbmr.3024. Epub 2016 Dec 27.

Epiprofin Regulates Enamel Formation and Tooth Morphogenesis by Controlling Epithelial-Mesenchymal Interactions During Tooth Development.

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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.
Institute of Oral Biology, Center of Dental Medicine, University of Zurich, Zurich, Switzerland.
Division of Orthopedic Research Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo, Japan.
Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai, Japan.
Department of Cell Biology and Histology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Spain.


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.



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