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.
Highlights
A significant number of discoveries have been advanced for the establishment of tooth position and patterning, critical developmental pathways that regulate cell and tissue formations, extracellular matrix formations, biomineralization, and the associated genes and gene families.A curious clinical aberration during craniofacial morphogenesis is the patterning and subsequent organogenesis of supernumerary tooth organs
We examined the expression of USAG-1 and Bone morphogenetic proteins (BMPs)-7 in the maxillary rudiment incisor tooth germ at E13–15 using USAG-1 +/LacZ and BMP-7+/LacZ mice
At E14, USAG-1 and BMP-7 transcripts were first detected in the mesenchymal cells of the maxillary rudimentary incisor (Fig. 1B, E, B’ and E’)
Summary
A significant number of discoveries have been advanced for the establishment of tooth position and patterning, critical developmental pathways that regulate cell and tissue formations, extracellular matrix formations, biomineralization, and the associated genes and gene families (see recent reviews by [1,2,3]). A curious clinical aberration during craniofacial morphogenesis is the patterning and subsequent organogenesis of supernumerary tooth organs. The term ‘‘supernumerary teeth’’ describes the production of more than the normal number of teeth in the human primary or permanent dentition. Normal mouse development presents a monophyodont dentition composed of one incisor and three molars in each quadrant. Mice have only molar and incisor tooth organs separated by a ‘‘toothless region’’ termed the diastema. Mice have a single primary dentition and their teeth are not replaced
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