title: Effects of Usag-1 and Bmp7 deficiencies on murine tooth morphogenesis.
abstract: BACKGROUND
  Wnt5a and Mrfzb1 genes are involved in the regulation of tooth size, and their expression levels are similar to that of Bmp7 during morphogenesis, including during the cap and early bell stages of tooth formation. We previously reported that Usag-1-deficient mice form supernumerary maxillary incisors. Thus, we hypothesized that BMP7 and USAG-1 signaling molecules may play important roles in tooth morphogenesis. In this study, we established double genetically modified mice to examine the in vivo inter-relationships between Bmp7 and Usag-1.
  
  
  RESULTS
  We measured the volume and cross-sectional areas of the mandibular incisors using micro-computed tomography (micro-CT) in adult Bmp7- and Usag-1-LacZ knock-in mice and their F2 generation upon interbreeding. The mandibular incisors of adult Bmp7+/- mice were significantly larger than those of wild-type (WT) mice. The mandibular incisors of adult Usag-1-/- mice were the largest of all genotypes examined. In the F2 generation, the effects of these genes were additive; Bmp7+/- was most strongly associated with the increase in tooth size using generalized linear models, and the total area of mandibular supernumerary incisors of Usag-1-/-Bmp7+/- mice was significantly larger than that of Usag-1-/-Bmp7 +/+ mice. At embryonic day 15 (E15), BrdU assays demonstrated that the labeling index of Bmp7+/- embryos was significantly higher than that of WT embryos in the cervical loop. Additionally, the labeling index of Usag-1-/- embryos was significantly the highest of all genotypes examined in dental papilla.
  
  
  CONCLUSIONS
  Bmp7 heterozygous mice exhibited significantly increased tooth sizes, suggesting that tooth size was controlled by specific gene expression. Our findings may be useful in applications of regenerative medicine and dentistry.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho 54, Sakyo-ku, Kyoto, 606-8397, Japan. kazuyuki@kuhp.kyoto-u.ac.jp.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho 54, Sakyo-ku, Kyoto, 606-8397, Japan.
authors.forename: Katsu
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: College of Liberal Arts and Sciences, Mie University, Mie, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Asahara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho 54, Sakyo-ku, Kyoto, 606-8397, Japan.
authors.forename: Honoka
authors.initials: H
authors.lastname: Kiso
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho 54, Sakyo-ku, Kyoto, 606-8397, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Togo
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho 54, Sakyo-ku, Kyoto, 606-8397, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: School of Dentistry and Health Sciences, Sturt University, Orange, Australia.
authors.forename: Boyen
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Molecular Genetics, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Sugai
authors.affiliation: Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Kyoto University Museum, Kyoto University, Kyoto, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Motokawa
authors.affiliation: Center for Craniofacial Molecular Biology, Division of Biomedical Sciences, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.
authors.forename: Harold C
authors.initials: HC
authors.lastname: Slavkin
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho 54, Sakyo-ku, Kyoto, 606-8397, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Bessho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging; D000818:Animals; D017209:Apoptosis; D055419:Bone Morphogenetic Protein 7 / Q000172:deficiency* / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000172:deficiency* / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D020287:In Situ Nick-End Labeling; D007180:Incisor / Q000000981:diagnostic imaging / Q000378:metabolism; D016014:Linear Models; D008297:Male; D008334:Mandible / Q000000981:diagnostic imaging / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008963:Molar / Q000378:metabolism; D009024:Morphogenesis; D009929:Organ Size; D010641:Phenotype; D013194:Staining and Labeling; D014070:Tooth / Q000000981:diagnostic imaging / Q000196:embryology* / Q000378:metabolism; D055114:X-Ray Microtomography; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C483887:Sostdc1 protein, mouse; D001616:beta-Galactosidase; D001973:Bromodeoxyuridine
keywords: Bmp7; Mouse model; Tooth morphogenesis; Tooth size; Tooth volume; Usag-1