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Interactions between BMP-7 and USAG-1 (uterine sensitization-associated gene-1) regulate supernumerary organ formations.

Kiso H, Takahashi K, Saito K, Togo Y, Tsukamoto H, Huang B, Sugai M, Shimizu A, Tabata Y, Economides AN, Slavkin HC, Bessho K - PLoS ONE (2014)

Bottom Line: BMP signaling in the rudimentary maxillary incisor, assessed by expressions of Msx1 and Dlx2 and the phosphorylation of Smad protein, was significantly enhanced.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan.

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.

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Related in: MedlinePlus

USAG-1 abrogation rescues apoptotic elimination of odontogenic mesenchymal cells.Sagittal sections of E15 embryo maxillary rudimentary incisor in transferase-mediated dUTP nick end-labelling method (TUNEL) staining; Cell nuclei were counterstained with Dapi (A–D), and TUNEL-positive cells in mesenchymal cells of maxillary rudimentary incisor (A’–D’). USAG-1+/+/BMP-7+/+, (A, A’); USAG-1−/−/BMP-7+/+, (B, B’); USAG-1+/+/BMP-7−/−, (C, C’) and USAG-1−/−/BMP-7−/− (D, D’). White line indicates the interface between epithelium and mesenchyme. The number of TUNEL-positive cells per section was counted in transverse section of USAG-1+/+/BMP-7+/+ (white bars), USAG-1−/−/BMP-7+/+ (right grey bars), USAG-1+/+/BMP-7−/− (dark grey bars), and USAG-1−/−/BMP-7−/− (black bars) mice (n = 3; E). USAG-1 abrogation rescued the apoptotic elimination of odontogenic mesenchymal cells in the tooth primordia of rudimentary maxillary incisor at E15, whereas these size are comparable (A, A’, B and B’). The apoptotic odontogenic mesenchymal cells in USAG-1−/−/BMP-7−/− are similar to USAG-1+/+/BMP-7+/+ in contrast to those in USAG-1−/−/BMP-7+/+ (A, A’, B, B’, D and D’).
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pone-0096938-g003: USAG-1 abrogation rescues apoptotic elimination of odontogenic mesenchymal cells.Sagittal sections of E15 embryo maxillary rudimentary incisor in transferase-mediated dUTP nick end-labelling method (TUNEL) staining; Cell nuclei were counterstained with Dapi (A–D), and TUNEL-positive cells in mesenchymal cells of maxillary rudimentary incisor (A’–D’). USAG-1+/+/BMP-7+/+, (A, A’); USAG-1−/−/BMP-7+/+, (B, B’); USAG-1+/+/BMP-7−/−, (C, C’) and USAG-1−/−/BMP-7−/− (D, D’). White line indicates the interface between epithelium and mesenchyme. The number of TUNEL-positive cells per section was counted in transverse section of USAG-1+/+/BMP-7+/+ (white bars), USAG-1−/−/BMP-7+/+ (right grey bars), USAG-1+/+/BMP-7−/− (dark grey bars), and USAG-1−/−/BMP-7−/− (black bars) mice (n = 3; E). USAG-1 abrogation rescued the apoptotic elimination of odontogenic mesenchymal cells in the tooth primordia of rudimentary maxillary incisor at E15, whereas these size are comparable (A, A’, B and B’). The apoptotic odontogenic mesenchymal cells in USAG-1−/−/BMP-7−/− are similar to USAG-1+/+/BMP-7+/+ in contrast to those in USAG-1−/−/BMP-7+/+ (A, A’, B, B’, D and D’).

Mentions: BMP-7 deficient mice die shortly after birth due to severe renal hypoplasia [38], [42]. To test the hypothesis that USAG-1 functions as a novel BMP-7 antagonist in maxillary supernumerary incisors formation, we analysed adult USAG-1−/−/BMP-7+/− mice. The incidence or pattern of supernumerary incisors formation in USAG-1−/−/BMP-7+/+ and USAG-1−/−/BMP-7+/− mice are almost identical, which was about 50% (Table S1). We previously demonstrated that the supernumerary maxillary incisor formed as a result of the successive development of the rudimentary incisor tooth primordia [15]. Therefore, we analysed the maxillary rudiment incisor tooth germ of USAG-1−/−/BMP-7−/−mice in select embryonic stages. We performed a series of histological investigations of USAG-1+/+/BMP-7+/+, USAG-1−/−/BMP-7+/+, USAG-1+/+/BMP-7−/− and USAG-1−/−/BMP-7−/− mice at E15 and newborn (P0). At E15, the area of the maxillary deciduous incisor was identified in wild type as well as all mutant mice in the labial border of the epithelial invagination (as described by [15], [51]). The size of rudimentary incisor is similar except USAG-1+/+/BMP-7−/− at E15 (Fig. 2A, A’, B, B’, C, C’, D, D’ and I). Rudimentary tooth primordia in USAG-1−/−/BMP-7−/− regressed and their size regressed and became smaller at birth. This was also observed for USAG-1+/+/BMP-7+/+ whereas the tooth organs in USAG-1−/−/BMP-7+/+ continued to develop and the enamel organ was formed (Fig. 2, E, E’, F, F’, H, H’ and J). USAG-1 abrogation rescued the apoptotic elimination of odontogenic mesenchymal cells in the rudimentary maxillary incisor tooth primordia at E15, whereas the size remained comparable (Fig. 3 A, A’, B and B’) [15]. The apoptotic mesenchymal cells in USAG-1−/−/BMP-7−/−are similar to USAG-1+/+/BMP-7+/+ in contrast to that of USAG-1−/−/BMP-7+/+ (Fig 3.A, A’, B, B’, D and D’). These results demonstrate that USAG-1 functions as a BMP-7 antagonist in maxillary supernumerary incisors formation.


Interactions between BMP-7 and USAG-1 (uterine sensitization-associated gene-1) regulate supernumerary organ formations.

Kiso H, Takahashi K, Saito K, Togo Y, Tsukamoto H, Huang B, Sugai M, Shimizu A, Tabata Y, Economides AN, Slavkin HC, Bessho K - PLoS ONE (2014)

USAG-1 abrogation rescues apoptotic elimination of odontogenic mesenchymal cells.Sagittal sections of E15 embryo maxillary rudimentary incisor in transferase-mediated dUTP nick end-labelling method (TUNEL) staining; Cell nuclei were counterstained with Dapi (A–D), and TUNEL-positive cells in mesenchymal cells of maxillary rudimentary incisor (A’–D’). USAG-1+/+/BMP-7+/+, (A, A’); USAG-1−/−/BMP-7+/+, (B, B’); USAG-1+/+/BMP-7−/−, (C, C’) and USAG-1−/−/BMP-7−/− (D, D’). White line indicates the interface between epithelium and mesenchyme. The number of TUNEL-positive cells per section was counted in transverse section of USAG-1+/+/BMP-7+/+ (white bars), USAG-1−/−/BMP-7+/+ (right grey bars), USAG-1+/+/BMP-7−/− (dark grey bars), and USAG-1−/−/BMP-7−/− (black bars) mice (n = 3; E). USAG-1 abrogation rescued the apoptotic elimination of odontogenic mesenchymal cells in the tooth primordia of rudimentary maxillary incisor at E15, whereas these size are comparable (A, A’, B and B’). The apoptotic odontogenic mesenchymal cells in USAG-1−/−/BMP-7−/− are similar to USAG-1+/+/BMP-7+/+ in contrast to those in USAG-1−/−/BMP-7+/+ (A, A’, B, B’, D and D’).
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pone-0096938-g003: USAG-1 abrogation rescues apoptotic elimination of odontogenic mesenchymal cells.Sagittal sections of E15 embryo maxillary rudimentary incisor in transferase-mediated dUTP nick end-labelling method (TUNEL) staining; Cell nuclei were counterstained with Dapi (A–D), and TUNEL-positive cells in mesenchymal cells of maxillary rudimentary incisor (A’–D’). USAG-1+/+/BMP-7+/+, (A, A’); USAG-1−/−/BMP-7+/+, (B, B’); USAG-1+/+/BMP-7−/−, (C, C’) and USAG-1−/−/BMP-7−/− (D, D’). White line indicates the interface between epithelium and mesenchyme. The number of TUNEL-positive cells per section was counted in transverse section of USAG-1+/+/BMP-7+/+ (white bars), USAG-1−/−/BMP-7+/+ (right grey bars), USAG-1+/+/BMP-7−/− (dark grey bars), and USAG-1−/−/BMP-7−/− (black bars) mice (n = 3; E). USAG-1 abrogation rescued the apoptotic elimination of odontogenic mesenchymal cells in the tooth primordia of rudimentary maxillary incisor at E15, whereas these size are comparable (A, A’, B and B’). The apoptotic odontogenic mesenchymal cells in USAG-1−/−/BMP-7−/− are similar to USAG-1+/+/BMP-7+/+ in contrast to those in USAG-1−/−/BMP-7+/+ (A, A’, B, B’, D and D’).
Mentions: BMP-7 deficient mice die shortly after birth due to severe renal hypoplasia [38], [42]. To test the hypothesis that USAG-1 functions as a novel BMP-7 antagonist in maxillary supernumerary incisors formation, we analysed adult USAG-1−/−/BMP-7+/− mice. The incidence or pattern of supernumerary incisors formation in USAG-1−/−/BMP-7+/+ and USAG-1−/−/BMP-7+/− mice are almost identical, which was about 50% (Table S1). We previously demonstrated that the supernumerary maxillary incisor formed as a result of the successive development of the rudimentary incisor tooth primordia [15]. Therefore, we analysed the maxillary rudiment incisor tooth germ of USAG-1−/−/BMP-7−/−mice in select embryonic stages. We performed a series of histological investigations of USAG-1+/+/BMP-7+/+, USAG-1−/−/BMP-7+/+, USAG-1+/+/BMP-7−/− and USAG-1−/−/BMP-7−/− mice at E15 and newborn (P0). At E15, the area of the maxillary deciduous incisor was identified in wild type as well as all mutant mice in the labial border of the epithelial invagination (as described by [15], [51]). The size of rudimentary incisor is similar except USAG-1+/+/BMP-7−/− at E15 (Fig. 2A, A’, B, B’, C, C’, D, D’ and I). Rudimentary tooth primordia in USAG-1−/−/BMP-7−/− regressed and their size regressed and became smaller at birth. This was also observed for USAG-1+/+/BMP-7+/+ whereas the tooth organs in USAG-1−/−/BMP-7+/+ continued to develop and the enamel organ was formed (Fig. 2, E, E’, F, F’, H, H’ and J). USAG-1 abrogation rescued the apoptotic elimination of odontogenic mesenchymal cells in the rudimentary maxillary incisor tooth primordia at E15, whereas the size remained comparable (Fig. 3 A, A’, B and B’) [15]. The apoptotic mesenchymal cells in USAG-1−/−/BMP-7−/−are similar to USAG-1+/+/BMP-7+/+ in contrast to that of USAG-1−/−/BMP-7+/+ (Fig 3.A, A’, B, B’, D and D’). These results demonstrate that USAG-1 functions as a BMP-7 antagonist in maxillary supernumerary incisors formation.

Bottom Line: BMP signaling in the rudimentary maxillary incisor, assessed by expressions of Msx1 and Dlx2 and the phosphorylation of Smad protein, was significantly enhanced.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan.

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.

Show MeSH
Related in: MedlinePlus