Sp6/Epiprofin is a master regulator in the developing tooth.
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ABSTRACT:
SUBMITTER: Rhodes CS
PROVIDER: S-EPMC8585705 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this study, whole-genome ChIP-seq analysis was performed to identify Sp6 regulatory targets from postnatal mouse molars. Enriched sequence reads (peaks) from Sp6 immunoprecipitations were located predominately adjacent to transcriptional start sites. Notably enriched for Sp6 peaks were genes highly-expressed in the tooth. Bioinformatic analysis of two pools of 1400 Sp6 enriched sequences identified a consensus nine-nucleotide DNA pulldown sequence of CTg/aTAATTA from mesenchyme and the nearly identical sequence, CTa/gTAATTA, from epithelium. Sp6 AT-rich interaction sequences are nearly identical to the ChIP-seq enriched sequences reported for Sp7 and Sp9. ChIP-seq analysis indicates Sp6 regulates a significant number of genes expressed in the tooth. GSE145909 is the original submission. GSE151391 is also from the same study. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151391
2021-11-23 | GSE145909 | GEO
Project description:BackgroundWe used an in vitro tooth development model to investigate the effects of overactivation of the Wnt/β-catenin pathway during odontogenesis by bromoindirubin oxime reagent (BIO), a specific inhibitor of GSK-3 activity.ResultsOveractivating the Wnt/β-catenin pathway at tooth initiation upregulated and ectopically expressed the epithelial markers Sonic Hedgehog (Shh), Epiprofin (Epfn), and Fibroblast growth factor8 (Fgf8), which are involved in the delimitation of odontogenic fields in the oral ectoderm. This result indicated an ectopic extension of the odontogenic potential. During tooth morphogenesis, Fibroblast growth factor4 (Fgf4), Fibroblast growth factor10 (Fgf10), Muscle segment homeobox 1 (Msx-1), Bone Morphogenetic protein 4 (Bmp4), and Dickkopf WNT signaling pathway inhibitor 1 (Dkk-1) were overexpressed in first molars cultured with BIO. Conversely, the expression levels of Wingless integration site 10b (Wnt-10b) and Shh were reduced. Additionally, the odontoblast differentiation markers Nestin and Epfn showed ectopic overexpression in the dental mesenchyme of BIO-treated molars. Moreover, alkaline phosphatase activity increased in the dental mesenchyme, again suggesting aberrant, ectopic mesenchymal cell differentiation. Finally, Bmp4 downregulated Epfn expression during dental morphogenesis.ConclusionsWe suggest the presence of a positive feedback loop wherein Epfn and β-catenin activate each other. The balance of the expression of these two molecules is essential for proper tooth development. We propose a possible link between Wnt, Bmp, and Epfn that would critically determine the correct patterning of dental cusps and the differentiation of odontoblasts and ameloblasts.
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Project description:A long-term goal is to bioengineer, fully functional, living teeth for regenerative medicine and dentistry applications. Biologically based replacement teeth would avoid insufficiencies of the currently used dental implants. Using natural tooth development as a guide, a model was fabricated using post-natal porcine dental epithelial (pDE), porcine dental mesenchymal (pDM) progenitor cells, and human umbilical vein endothelial cells (HUVEC) encapsulated within gelatin methacrylate (GelMA) hydrogels. Previous publications have shown that post-natal DE and DM cells seeded onto synthetic scaffolds exhibited mineralized tooth crowns composed of dentin and enamel. However, these tooth structures were small and formed within the pores of the scaffolds. The present study shows that dental cell-encapsulated GelMA constructs can support mineralized dental tissue formation of predictable size and shape. Individually encapsulated pDE or pDM cell GelMA constructs were analysed to identify formulas that supported pDE and pDM cell attachment, spreading, metabolic activity, and neo-vasculature formation with co-seeded endothelial cells (HUVECs). GelMa constructs consisting of pDE-HUVECS in 3% GelMA and pDM-HUVECs within 5% GelMA supported dental cell differentiation and vascular mineralized dental tissue formation in vivo. These studies are the first to demonstrate the use of GelMA hydrogels to support the formation of post-natal dental progenitor cell-derived mineralized and functionally vascularized tissues of specified size and shape. These results introduce a novel three-dimensional biomimetic tooth bud model for eventual bioengineered tooth replacement teeth in humans. Copyright © 2017 John Wiley & Sons, Ltd.
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Project description:BackgroundAmeloblasts are epithelially derived cells responsible for enamel formation through a process known as amelogenesis. Amongst the several transcription factors that are expressed during amelogenesis, both Msx2 and Sp6 transcription factors play important role. Msx2 and Sp6 mouse mutants, exhibit similar amelogenesis defects, namely enamel hypoplasia, while humans with amelogenesis imperfecta (AI) carry mutations in the human homologues of MSX2 or SP6 genes. These across species similarities in function indicate that these two transcription factors may reside in the same developmental pathway. In this paper, we test whether they work in a coordinated manner to exert their effect during amelogenesis.MethodsTwo different dental epithelial cell lines, the mouse LS8 and the rat G5 were used for either overexpression or silencing of Msx2 or Sp6 or both. Msx2 mutant mouse embryos or pups were used for in vivo studies. In situ hybridization, semi-quantitative and quantitative real time PCR were employed to study gene expression pattern. MatInspector was used to identify several potential putative Msx2 binding sites upstream of the murine Sp6 promoter region. Chromatin Immunoprecipitation (chIP) was used to confirm the binding of Msx2 to Sp6 promoter at the putative sites.ResultsUsing the above methods we identified that (i) Msx2 and Sp6 exhibit overlapping expression in secretory ameloblasts, (ii) Sp6 expression is reduced in the Msx2 mouse mutant secretoty ameloblasts, and (iii) that Msx2, like Sp6 inhibits follistatin expression. Specifically, our loss-of function studies by silencing Msx2 and/or Sp6 in mouse dental epithelial (LS8) cells showed significant downregulation of Sp6 but upregulation of Fst expression. Transient transfection of Msx2 overexpression plasmid, up-regulated Sp6 and downregulated Fst expression. Additionally, using MatInspector, we identified several potential putative Msx2 binding sites, 3.5 kb upstream of the murine Sp6 promoter region. By chIP, we confirmed the binding of Msx2 to Sp6 promoter at these sites, thus suggesting that Sp6 is a direct target of Msx2.ConclusionCollectively, these results show that Sp6 and Msx2 work in a concerted manner to form part of a network of transcription factors that operate during later stages of tooth development controlling ameloblast life cycle and amelogenesis.
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