title: Mutant GDF5 enhances ameloblast differentiation via accelerated BMP2-induced Smad1/5/8 phosphorylation.
abstract: Bone morphogenetic proteins (BMPs) regulate hard tissue formation, including bone and tooth. Growth differentiation factor 5 (GDF5), a known BMP, is expressed in cartilage and regulates chondrogenesis, and mutations have been shown to cause osteoarthritis. Notably, GDF5 is also expressed in periodontal ligament tissue; however, its role during tooth development is unclear. Here, we used cell culture and in vivo analyses to determine the role of GDF5 during tooth development. GDF5 and its associated BMP receptors are expressed at the protein and mRNA levels during postnatal tooth development, particularly at a stage associated with enamel formation. Furthermore, whereas BMP2 was observed to induce evidently the differentiation of enamel-forming ameloblasts, excess GDF5 induce mildly this differentiation. A mouse model harbouring a mutation in GDF5 (W408R) showed enhanced enamel formation in both the incisors and molars, but not in the tooth roots. Overexpression of the W408R GDF5 mutant protein was shown to induce BMP2-mediated mRNA expression of enamel matrix proteins and downstream phosphorylation of Smad1/5/8. These results suggest that mutant GDF5 enhances ameloblast differentiation via accelerated BMP2-signalling.
authors.affiliation: Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China.|Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.|Department of Pediatric Dentistry, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Saito
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.|Division of Pediatric Dentistry and Special Needs Dentistry, Department of Developmental Oral Health Science, Iwate Medical University, Morioka 020-8505, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Maruya
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Fukumoto
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Section of Orthodontics and Dentofacial Orthopedics, Department of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka 812-8582, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Miyazaki
authors.affiliation: Section of Orthodontics and Dentofacial Orthopedics, Department of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka 812-8582, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Yoshizaki
authors.affiliation: Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Ge
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukumoto
mesh_terms: D000565:Ameloblasts / Q000166:cytology / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D003743:Dental Enamel / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055428:Growth Differentiation Factor 5 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009805:Odontogenesis / Q000235:genetics; D010766:Phosphorylation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics* / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics* / Q000378:metabolism; D051904:Smad8 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; C525894:Gdf5 protein, mouse; D055428:Growth Differentiation Factor 5; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse