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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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BMP-7 co-localization with USAG-1 in the mesenchymal and epithelial cells of maxillary rudimentary incisor.(A–F) Whole-mount X-Gal expression in tooth germs of E13 –15 maxillary. (A’–F’) Parasagittal sections (anterior to the left) of the tooth germs from panels A–F show X-Gal expression in the rudimentary incisor epithelium. USAG-1 (A–C, A’–C’) and BMP-7 (D–F, D’–F’) were expressed in the tooth organ of rudimentary maxillary incisor (red arrow) in addition to the tooth organ of characteristic incisor (black arrow). At E13, USAG-1 and BMP-7 transcripts were prominent in the labial epithelium in addition to the dental epithelium (A, D, A’ and D’). At E14, USAG-1 and BMP-7 started to be expressed in the mesenchymal cells of the maxillary rudimentary incisor to the surface of the epithelium (B, E, B’ and E’). At E15, the expression of both USAG-1 and BMP-7 increased in the mesenchymal cells of the maxillary rudimentary incisor (C, F, C’ and F’). BMP-7 co-localized with USAG-1 in the area of the tooth germ of maxillary rudimentary incisor in addition to the tooth organ of regular maxillary incisor. White dotted line indicates the interface between epithelium and mesenchyme.
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pone-0096938-g001: BMP-7 co-localization with USAG-1 in the mesenchymal and epithelial cells of maxillary rudimentary incisor.(A–F) Whole-mount X-Gal expression in tooth germs of E13 –15 maxillary. (A’–F’) Parasagittal sections (anterior to the left) of the tooth germs from panels A–F show X-Gal expression in the rudimentary incisor epithelium. USAG-1 (A–C, A’–C’) and BMP-7 (D–F, D’–F’) were expressed in the tooth organ of rudimentary maxillary incisor (red arrow) in addition to the tooth organ of characteristic incisor (black arrow). At E13, USAG-1 and BMP-7 transcripts were prominent in the labial epithelium in addition to the dental epithelium (A, D, A’ and D’). At E14, USAG-1 and BMP-7 started to be expressed in the mesenchymal cells of the maxillary rudimentary incisor to the surface of the epithelium (B, E, B’ and E’). At E15, the expression of both USAG-1 and BMP-7 increased in the mesenchymal cells of the maxillary rudimentary incisor (C, F, C’ and F’). BMP-7 co-localized with USAG-1 in the area of the tooth germ of maxillary rudimentary incisor in addition to the tooth organ of regular maxillary incisor. White dotted line indicates the interface between epithelium and mesenchyme.

Mentions: USAG-1 transcript expression was detected in the area of the maxillary rudiment incisor tooth germ in addition to the regular maxillary incisor tooth organ by in situ hybridization [15]. We examined the expression of USAG-1 and BMP-7 in the maxillary rudiment incisor tooth germ at E13–15 using USAG-1 +/LacZ and BMP-7+/LacZ mice. At E13 (late bud stage), USAG-1 and BMP-7 transcripts were prominent in the labial epithelium in addition to the enamel organ epithelium (Fig. 1A, D, A’ and D). At E14 (early cap stage), USAG-1 and BMP-7 transcripts were first detected in the mesenchymal cells of the maxillary rudimentary incisor (Fig. 1B, E, B’ and E’). At E15 (cap stage), USAG-1 and BMP-7 expression increased in the mesenchymal cells of the maxillary incisor tooth organ (Fig. 1C, F, C’ and F’). BMP-7 co-localized with USAG-1 in the area of the maxillary rudiment incisor tooth organ in addition to the conventional maxillary incisor tooth organ.


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)

BMP-7 co-localization with USAG-1 in the mesenchymal and epithelial cells of maxillary rudimentary incisor.(A–F) Whole-mount X-Gal expression in tooth germs of E13 –15 maxillary. (A’–F’) Parasagittal sections (anterior to the left) of the tooth germs from panels A–F show X-Gal expression in the rudimentary incisor epithelium. USAG-1 (A–C, A’–C’) and BMP-7 (D–F, D’–F’) were expressed in the tooth organ of rudimentary maxillary incisor (red arrow) in addition to the tooth organ of characteristic incisor (black arrow). At E13, USAG-1 and BMP-7 transcripts were prominent in the labial epithelium in addition to the dental epithelium (A, D, A’ and D’). At E14, USAG-1 and BMP-7 started to be expressed in the mesenchymal cells of the maxillary rudimentary incisor to the surface of the epithelium (B, E, B’ and E’). At E15, the expression of both USAG-1 and BMP-7 increased in the mesenchymal cells of the maxillary rudimentary incisor (C, F, C’ and F’). BMP-7 co-localized with USAG-1 in the area of the tooth germ of maxillary rudimentary incisor in addition to the tooth organ of regular maxillary incisor. White dotted line indicates the interface between epithelium and mesenchyme.
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pone-0096938-g001: BMP-7 co-localization with USAG-1 in the mesenchymal and epithelial cells of maxillary rudimentary incisor.(A–F) Whole-mount X-Gal expression in tooth germs of E13 –15 maxillary. (A’–F’) Parasagittal sections (anterior to the left) of the tooth germs from panels A–F show X-Gal expression in the rudimentary incisor epithelium. USAG-1 (A–C, A’–C’) and BMP-7 (D–F, D’–F’) were expressed in the tooth organ of rudimentary maxillary incisor (red arrow) in addition to the tooth organ of characteristic incisor (black arrow). At E13, USAG-1 and BMP-7 transcripts were prominent in the labial epithelium in addition to the dental epithelium (A, D, A’ and D’). At E14, USAG-1 and BMP-7 started to be expressed in the mesenchymal cells of the maxillary rudimentary incisor to the surface of the epithelium (B, E, B’ and E’). At E15, the expression of both USAG-1 and BMP-7 increased in the mesenchymal cells of the maxillary rudimentary incisor (C, F, C’ and F’). BMP-7 co-localized with USAG-1 in the area of the tooth germ of maxillary rudimentary incisor in addition to the tooth organ of regular maxillary incisor. White dotted line indicates the interface between epithelium and mesenchyme.
Mentions: USAG-1 transcript expression was detected in the area of the maxillary rudiment incisor tooth germ in addition to the regular maxillary incisor tooth organ by in situ hybridization [15]. We examined the expression of USAG-1 and BMP-7 in the maxillary rudiment incisor tooth germ at E13–15 using USAG-1 +/LacZ and BMP-7+/LacZ mice. At E13 (late bud stage), USAG-1 and BMP-7 transcripts were prominent in the labial epithelium in addition to the enamel organ epithelium (Fig. 1A, D, A’ and D). At E14 (early cap stage), USAG-1 and BMP-7 transcripts were first detected in the mesenchymal cells of the maxillary rudimentary incisor (Fig. 1B, E, B’ and E’). At E15 (cap stage), USAG-1 and BMP-7 expression increased in the mesenchymal cells of the maxillary incisor tooth organ (Fig. 1C, F, C’ and F’). BMP-7 co-localized with USAG-1 in the area of the maxillary rudiment incisor tooth organ in addition to the conventional maxillary incisor tooth organ.

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