title: Interactions between BMP-7 and USAG-1 (uterine sensitization-associated gene-1) regulate supernumerary organ formations.
abstract: Bone morphogenetic proteins (BMPs) are highly conserved signaling molecules that are part of the transforming growth factor (TGF)-beta superfamily, and function in the patterning and morphogenesis of many organs including development of the dentition. The functions of the BMPs are controlled by certain classes of molecules that are recognized as BMP antagonists that inhibit BMP binding to their cognate receptors. In this study we tested the hypothesis that USAG-1 (uterine sensitization-associated gene-1) suppresses deciduous incisors by inhibition of BMP-7 function. We learned that USAG-1 and BMP-7 were expressed within odontogenic epithelium as well as mesenchyme during the late bud and early cap stages of tooth development. USAG-1 is a BMP antagonist, and also modulates Wnt signaling. USAG-1 abrogation rescued apoptotic elimination of odontogenic mesenchymal cells. BMP signaling in the rudimentary maxillary incisor, assessed by expressions of Msx1 and Dlx2 and the phosphorylation of Smad protein, was significantly enhanced. Using explant culture and subsequent subrenal capsule transplantation of E15 USAG-1 mutant maxillary incisor tooth primordia supplemented with BMP-7 demonstrated in USAG-1+/- as well as USAG-1-/- rescue and supernumerary tooth development. Based upon these results, we conclude that USAG-1 functions as an antagonist of BMP-7 in this model system. These results further suggest that the phenotypes of USAG-1 and BMP-7 mutant mice reported provide opportunities for regenerative medicine and dentistry.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 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, Sakyo-ku, Kyoto, Japan.
authors.forename: Katsu
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan.
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, Sakyo-ku, Kyoto, 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, Sakyo-ku, Kyoto, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Department of Paediatric Dentistry, School of Medicine and Dentistry, James Cook University, Cairns, Australia.
authors.forename: Boyen
authors.initials: B
authors.lastname: Huang
authors.affiliation: Translational Research Center, Kyoto University Hospital, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Sugai
authors.affiliation: Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York, United States of America.
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.affiliation: Center for Craniofacial Molecular Biology, Division of Biomedical Sciences, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, United States of America.
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, Sakyo-ku, Kyoto, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Bessho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000172:deficiency / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D007180:Incisor / Q000196:embryology; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D038081:Organogenesis; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D014096:Tooth, Supernumerary / Q000196:embryology* / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C483887:Sostdc1 protein, mouse