Abstract
BackgroundWnt5a 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.ResultsWe 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.ConclusionsBmp7 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-016-0117-x) contains supplementary material, which is available to authorized users.
Highlights
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
In this study, we examined the effects of BMP7 and Uterine sensitization-associated gene-1 (USAG-1) signaling on tooth size in mandibular incisors using the F2 generation of mice
Expression of Bmp7 and Usag-1 at E14 and embryonic day 15 (E15) Sections from Bmp7+/− mice indicated that Bmp7 was expressed in the mesenchyme around the tooth germ (Fig. 1a, d, g), rudimentary incisor (Fig. 1a, d), and enamel knot (Fig. 1b, e)
Summary
Wnt5a and Mrfzb genes are involved in the regulation of tooth size, and their expression levels are similar to that of Bmp during morphogenesis, including during the cap and early bell stages of tooth formation. Development of the dentition is regulated by time- and position-specific reciprocal epithelial-mesenchymal interactions [1,2,3,4]. These odontogenic interactions are directed and coordinated by transcription factors, growth and signaling factors, their cognate receptors, and extracellular matrix constituents [5]. Various combinations of molecules within these interactions determine when or where teeth develop and modulate the specifications for tooth size and shape. LRP4 modulates and integrates BMP and canonical Wnt signaling during tooth morphogenesis by binding to secreted USAG-1 [24]. We previously reported that Usag-1-deficient mice exhibit supernumerary maxillary incisors in response to enhanced BMP signaling and that BMP signaling is modulated by Wnt signaling in Usag-1-deficient mice [26, 27]
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