RUNX transcription factors orchestrate many different aspects of biology, including basic cellular and developmental processes, stem cell biology and tumorigenesis. In this Primer, we introduce the molecular hallmarks of the three mammalian RUNX genes, RUNX1, RUNX2 and RUNX3, and discuss the regulation of their activities and their mechanisms of action. We then review their crucial roles in the specification and maintenance of a wide array of tissues during embryonic development and adult homeostasis.

RUNX transcription factors: orchestrators of development

Tracing the skeletal progenitor transition during postnatal bone formation.

Dental caries, a chronic and irreversible disease caused by caries-causing bacteria, has been listed as one of the three major human diseases to be prevented and treated. Therefore, it is critical to effectively stop the development of enamel caries. Remineralization treatment can control the progression of caries by inhibiting and reversing enamel demineralization at an early stage. In this process, functional materials guide the deposition of minerals on the damaged enamel, and the structure and hardness of the enamel are then restored. These remineralization materials have great potential for clinical application. In this review, advanced materials for enamel remineralization were briefly summarized, furthermore, an outlook on the perspective of remineralization materials were addressed.

Advanced materials for enamel remineralization

Runt-related transcription factor 2 (Runx2) is involved in the early stage of tooth development. However, only few studies have reported the role of Runx2 in enamel development, which may be attributed to that Runx2 full knockout mice cannot survive after birth. In the present study, we successfully established a Runx2-deficient mouse model using a conditional knockout (cKO) method. We observed a significant reduction in the degree of mineralization and the decreased size of enamel rods in cKO mice. Histological analysis showed the retained enamel proteins in enamel layer at maturation stage in cKO molars. Further analysis by qRT-PCR revealed that the expressions of genes encoding enamel structure proteins, such as amelogenin (AMELX), ameloblastin (AMBN) and enamelin (ENAM), were increased in cKO enamel organs. On the other hand, the expression of kallikrein-related peptidase-4 (KLK4) at the mRNA and protein levels was dramatically decreased from late secretory stage to maturation stage in cKO enamel organs, while the expression of matrix metalloproteinase-20 (MMP-20) was not significantly altered. Finally, immunohistochemistry indicated that the uptake of amelogenins by ameloblasts was significantly decreased in cKO mice. Taken together, Runx2 played critical roles in controlling enamel maturation by increasing synthesis of KLK4 and decreasing synthesis of AMELX, AMBN and ENAM.

/pdf/ablation-of-runx2-in-ameloblasts-suppresses-enamel-53durzxku0.pdf

Ablation of Runx2 in Ameloblasts Suppresses Enamel Maturation in Tooth Development.

Dental enamel is hardest tissue in the body and is produced by dental epithelial cells residing in the tooth. Their cell fates are tightly controlled by transcriptional programs that are facilitated by fate determining transcription factors and chromatin regulators. Understanding the transcriptional program controlling dental cell fate is critical for our efforts to build and repair teeth. In this review, we describe the current understanding of these regulators essential for regeneration of dental epithelial stem cells and progeny, which are identified through transgenic mouse models. We first describe the development and morphogenesis of mouse dental epithelium in which different subpopulations of epithelia such as ameloblasts contribute to enamel formation. Then, we describe the function of critical factors in stem cells or progeny to drive enamel lineages. We also show that gene mutations of these factors are associated with dental anomalies in craniofacial diseases in humans. We also describe the function of the master regulators to govern dental lineages, in which the genetic removal of each factor switches dental cell fate to that generating hair. The distinct and related mechanisms responsible for the lineage plasticity are discussed. This knowledge will lead us to develop a potential tool for bioengineering new teeth.

/pdf/transcriptional-regulation-of-dental-epithelial-cell-fate-158krbzhok.pdf

Transcriptional Regulation of Dental Epithelial Cell Fate.

Matrix metalloproteinase-20 (Mmp20) plays an essential role in amelogenesis during tooth development and is regulated by transforming growth factor-β1 (TGF-β1) in mouse ameloblast lineage cells (ALCs). The objective of this study was to explore the role of myocyte enhancer factor-2C (MEF2C), a key transcription factor in craniofacial development, in TGF-β1-induced Mmp20 gene expression. We investigated Mmp20 expression in ALCs over-expressing MEF2C and in ALCs with MEF2C knocked down. We also analyzed activity of the Mmp20 promoter using a transient reporter gene-expression assay in cultured ALCs. Putative transcription factor-binding sites for MEF2C and TGF-β1 on the Mmp20 promoter were analyzed with bioinformatics tools and examined using an electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). The expression of Mmp20 was induced, in a dose-dependent manner, by MEF2C over-expression, and TGF-β1-induced Mmp20 expression was blocked by MEF2C knockdown in ALCs. There was a TGF-β1/MEF2C-responsive region, including a putative MEF2-binding site, between base pairs -356 and -73 of the Mmp20 promoter. Mutation of the putative MEF2-binding site significantly reduced Mmp20 promoter activity upon activation with MEF2C or TGF-β1. In conclusion, TGF-β1-induced Mmp20 expression in ALCs was regulated through the MEF2-binding site on the Mmp20 promoter and thus mediated by the MEF2C signaling pathway.

Transforming growth factor-β1 regulates expression of the matrix metalloproteinase 20 (Mmp20) gene through a mechanism involving the transcription factor, myocyte enhancer factor-2C, in ameloblast lineage cells.

Amelotin (Amtn) is a recently identified enamel protein secreted by ameloblasts at late stage of enamel development. Runt‑related transcription factor 2 (Runx2) in combination with the coactivator core‑binding factor β (Cbfβ) regulates the early stages of tooth development. The aim of the present study was to investigate the role of Runx2 in the regulation of Amtn gene expression in ameloblasts. Immunohistochemistry was performed and the results revealed that Runx2 protein was predominantly expressed in the nuclei of ameloblasts during the transition stage and the maturation stage of enamel development, whereas Cbfβ was expressed in ameloblasts from the secretory stage to the maturation stage. Reverse transcription‑quantitative polymerase chain reaction results demonstrated that Runx2 knockdown decreased Amtn expression in ameloblast‑lineage cells and co‑expression of Runx2 and Cbfβ in ameloblast lineage cells induced an upregulation in Amtn gene expression. Two putative Runx2‑binding sites within the Amtn promoter were identified using bioinformatics analysis. Results of an electrophoretic mobility shift assay and chromatin immunoprecipitation indicated that Runx2/Cbfβ bound to specific DNA sequences. Site‑directed mutagenesis of the Runx2 binding sites within the Amtn promoter resulted in decreased basal promoter activity and did not affect the overexpressed Runx2/Cbfβ. The results of the present study suggest that Runx2 upregulates Amtn gene expression via binding directly to Runx2 sites within the Amtn promoter during amelogenesis.

/pdf/combination-of-runx2-and-cbfb-upregulates-amelotin-gene-3n2vzbv5pv.pdf

Combination of Runx2 and Cbfβ upregulates Amelotin gene expression in ameloblasts by directly interacting with cis‑enhancers during amelogenesis.

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Ablation of Runx2 in Ameloblasts Suppresses Enamel Maturation in Tooth Development.

Transforming growth factor-β1 regulates expression of the matrix metalloproteinase 20 (Mmp20) gene through a mechanism involving the transcription factor, myocyte enhancer factor-2C, in ameloblast lineage cells.

Combination of Runx2 and Cbfβ upregulates Amelotin gene expression in ameloblasts by directly interacting with cis‑enhancers during amelogenesis.