During development, tooth germs undergo various morphological changes resulting from interactions between the oral epithelium and ectomesenchyme. These processes are influenced by the extracellular matrix, the composition of which, along with cell adhesion and signaling, is regulated by metalloproteinases. Notably, these include matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs). Our analysis of previously published scRNAseq datasets highlight that these metalloproteinases show dynamic expression patterns during tooth development, with expression in a wide range of cell types, suggesting multiple roles in tooth morphogenesis. To investigate this, Marimastat, a broad-spectrum inhibitor of MMPs, ADAMs, and ADAMTSs, was applied to ex vivo cultures of mouse molar tooth germs. The treated samples exhibited significant changes in tooth germ size and morphology, including an overall reduction in size and an inversion of the typical bell shape. The cervical loop failed to extend, and the central area of the inner enamel epithelium protruded. Marimastat treatment also disrupted proliferation, cell polarization, and organization compared with control tooth germs. In addition, a decrease in laminin expression was observed, leading to a disruption in continuity of the basement membrane at the epithelial-mesenchymal junction. Elevated hypoxia-inducible factor 1-alpha gene (Hif-1α) expression correlated with a disruption to blood vessel development around the tooth germs. These results reveal the crucial role of metalloproteinases in tooth growth, shape, cervical loop elongation, and the regulation of blood vessel formation during prenatal tooth development.NEW & NOTEWORTHY Inhibition of metalloproteinases during tooth development had a wide-ranging impact on molar growth affecting proliferation, cell migration, and vascularization, highlighting the diverse role of these proteins in controlling development.

• MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit metabolism   genetics   MeSH
• Matrix Metalloproteinase Inhibitors pharmacology   MeSH
• Hydroxamic Acids pharmacology   MeSH
• Metalloproteases metabolism   genetics   MeSH
• Molar embryology   growth & development   metabolism   enzymology   MeSH
• Morphogenesis MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Odontogenesis * MeSH
• Cell Proliferation * MeSH
• Gene Expression Regulation, Developmental MeSH
• Tooth Germ embryology   metabolism   enzymology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Development of dentition is a commonly studied process as a representative of the development of ectodermal derivates. A key step is the formation of a signaling center called the enamel knot (EK), which organizes tooth crown formation. In the mouse lower jaw, the anterior part of the tooth-forming region undergoes a series of complex events before the first molar primary EK can form more posteriorly and the tooth can progress through the cap stage. Although much is known about the molecular factors involved in tooth development, disentangling their specific roles is difficult. In this study, we circumvented this problem by isolating the posterior part of the tooth-forming region at embryonic day 13.5 and cultivating it in vitro. By treating them with molecules activating or inhibiting Sonic hedgehog (Shh) and fibroblast growth factor (Fgf) pathways, we demonstrate that Shh plays the role of an inhibitor of EK formation, and we suggest that the FGF pathways may have both positive and negative roles, as seen in hair. By RNA-sequencing of the cultivated isolates after 0, 16, or 24 h in vitro, respectively, we screened for genes whose expression varies with EK and cap formation and pointed to Cdkn2b and Sema3b as 2 promising candidates in this process.

• MeSH
• Fibroblast Growth Factors physiology   MeSH
• Molar embryology   MeSH
• Mice MeSH
• Odontogenesis * physiology   genetics   MeSH
• Hedgehog Proteins physiology   metabolism   MeSH
• Signal Transduction MeSH
• Gene Expression Regulation, Developmental MeSH
• Tooth Crown * embryology   MeSH
• Dental Enamel * embryology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: Dental caries is a widespread multifactorial disease, caused by the demineralization of hard dental tissues. Susceptibility to dental caries is partially genetically conditioned; this study was aimed at finding an association of selected single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in amelogenesis with this disease in children. MATERIALS AND METHODS: In this case-control study, 15 SNPs in ALOX15, AMBN, AMELX, KLK4, TFIP11, and TUFT1 genes were analyzed in 150 children with primary dentition and 611 children with permanent teeth with/without dental caries from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) cohort. RESULTS: Dental caries in primary dentition was associated with SNPs in AMELX (rs17878486) and KLK4 (rs198968, rs2242670), and dental caries in permanent dentition with SNPs in AMELX (rs17878486) and KLK4 (rs2235091, rs2242670, rs2978642), (p ≤ 0.05). No significant differences between cases and controls were observed in the allele or genotype frequencies of any of the selected SNPs in ALOX15, AMBN, TFIP11, and TUFT1 genes (p > 0.05). Some KLK4 haplotypes were associated with dental caries in permanent dentition (p ≤ 0.05). CONCLUSIONS: Based on this study, we found that although the SNPs in AMELX and KLK4 are localized in intronic regions and their functional significance has not yet been determined, they are associated with susceptibility to dental caries in children. CLINICAL RELEVANCE: AMELX and KLK4 variants could be considered in the risk assessment of dental caries, especially in permanent dentition, in the European Caucasian population.

• MeSH
• Amelogenesis * genetics   MeSH
• Amelogenin genetics   MeSH
• Child MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Case-Control Studies MeSH
• Dental Caries * genetics   epidemiology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH

Úvod a cíl: Lidská dentice je předmětem odborného zájmu stomatologie i dentální antropologie a je zdrojem informací o evoluci člověka, rozmanitosti lidských populací i individuálním vývoji nebo patologiích. Oba obory se často zaměřují na klinicky viditelný výsledek fylogeneze a ontogeneze: korunku zubu. Korunka zubu zejména posteriorní dentice, tedy premolárů nebo molárů, se vyznačuje komplexní morfologií, která je výsledkem iterativních procesů genetické, epigenetické a environmentální povahy. Po vytvoření korunky se její morfologie již nemění. Výjimkou je destrukce tvrdých tkání, která může být způsobena zubním kazem, atricí nebo abrazí, případně traumatem. Velikost a tvar zubu jsou tradičně zkoumány pomocí lineárních rozměrů nebo observací a hodnocením stupně projevu morfologických znaků. S rozvojem moderních zobrazovacích technologií a jejich dostupností se rozvíjí také využití alternativních metodologických přístupů pro popis morfologie korunky zubu. Tyto metody nabízí nové možnosti studia variability velikosti a tvaru dentice a mohou být pro popis morfologie zubů a biologický základ její variability vhodnější. Cílem sdělení je popsat a shrnout současné trendy kvantifikace variability dentice v dentální antropologii. Metodika: Studie byla založena na rešerši odborné literatury zaměřené na morfologii lidské dentice a přístupy dentální antropologie k jejímu studiu. Využito bylo zejména databází Web of Science a PubMed. Závěr: Přehledový článek se zabývá metodami kvantifikace morfologie lidské dentice a jejich využitím s ohledem na vývoj morfologie zubu.

Introduction and aim: Human dentition is an object of interest of both dentistry and dental anthropology, and a source of diverse information about human evolution, variability of populations, individual development or pathological cases. Both subjects often study the clinically visible result of phylogeny and ontogeny: a tooth crown. Tooth crown especially of the posterior dentition, i.e., premolars and molars, is characterized by complex morphology which is formed by iterative processes of genetic, epigenetic, and environmental character. After its completion, a tooth crown can be altered only by destruction of hard tissues, e.g., dental caries, trauma or tooth wear. Size and shape of tooth crown is traditionally studied by linear dimensions or by observation and scoring of the discrete morphological traits. With the expansion of modern imaging technologies, new methodological approaches are used increasingly. These approaches are more suitable for describing the variation of dentition and their results are potentially more informative about the biological basis of dental variability. The aim of this study is to describe and summarize the current trends of tooth morphology quantification in dental anthropology. Methods: Study was based on the survey of research papers and books focused on tooth morphology and approaches of dental anthropology to its study. Mostly the Web of Science and PubMed databases were used for the survey. Conclusion: The review is focused on the methods of quantification of human dental morphology and their use with respect to the development of tooth morphology.

• Keywords
• dentální antropologie, velikost a tvar zubu, morfometrie,
• MeSH
• Dentition * MeSH
• Humans MeSH
• Odontogenesis * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Considerable amount of research has been focused on dentin mineralization, odontoblast differentiation, and their application in dental tissue engineering. However, very little is known about the differential role of functionally and spatially distinct types of dental epithelium during odontoblast development. Here we show morphological and functional differences in dentin located in the crown and roots of mouse molar and analogous parts of continuously growing incisors. Using a reporter (DSPP-cerulean/DMP1-cherry) mouse strain and mice with ectopic enamel (Spry2+/- ;Spry4-/- ), we show that the different microstructure of dentin is initiated in the very beginning of dentin matrix production and is maintained throughout the whole duration of dentin growth. This phenomenon is regulated by the different inductive role of the adjacent epithelium. Thus, based on the type of interacting epithelium, we introduce more generalized terms for two distinct types of dentins: cementum versus enamel-facing dentin. In the odontoblasts, which produce enamel-facing dentin, we identified uniquely expressed genes (Dkk1, Wisp1, and Sall1) that were either absent or downregulated in odontoblasts, which form cementum-facing dentin. This suggests the potential role of Wnt signalling on the dentin structure patterning. Finally, we show the distribution of calcium and magnesium composition in the two developmentally different types of dentins by utilizing spatial element composition analysis (LIBS). Therefore, variations in dentin inner structure and element composition are the outcome of different developmental history initiated from the very beginning of tooth development. Taken together, our results elucidate the different effects of dental epithelium, during crown and root formation on adjacent odontoblasts and the possible role of Wnt signalling which together results in formation of dentin of different quality. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

• MeSH
• Cell Differentiation MeSH
• Dentin * MeSH
• Epithelium MeSH
• Extracellular Matrix Proteins genetics   MeSH
• Mice MeSH
• Odontoblasts * MeSH
• Odontogenesis MeSH
• Incisor MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Tooth formation requires complex signaling interactions both within the oral epithelium and between the epithelium and the underlying mesenchyme. Previous studies of the Wnt/β-catenin pathway have shown that tooth formation is partly inhibited in loss-of-function mutants, and gain-of-function mutants have perturbed tooth morphology. However, the stage at which Wnt signaling is first important in tooth formation remains unclear. Here, using an Fgf8-promoter-driven, and therefore early, deletion of β-catenin in mouse molar epithelium, we found that loss of Wnt/β-catenin signaling completely deletes the molar tooth, demonstrating that this pathway is central to the earliest stages of tooth formation. Early expression of a dominant-active β-catenin protein also perturbs tooth formation, producing a large domed evagination at early stages and supernumerary teeth later on. The early evaginations are associated with premature mesenchymal condensation marker, and are reduced by inhibition of condensation-associated collagen synthesis. We propose that invagination versus evagination morphogenesis is regulated by the relative timing of epithelial versus mesenchymal cell convergence regulated by canonical Wnt signaling. Together, these studies reveal new aspects of Wnt/β-catenin signaling in tooth formation and in epithelial morphogenesis more broadly.

• MeSH
• beta Catenin metabolism   MeSH
• Epithelium metabolism   MeSH
• Epithelial Cells cytology   metabolism   MeSH
• Mesoderm metabolism   MeSH
• Molar cytology   growth & development   metabolism   MeSH
• Morphogenesis physiology   MeSH
• Mice MeSH
• Odontogenesis genetics   physiology   MeSH
• Cell Proliferation MeSH
• Wnt Signaling Pathway physiology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH

Like all developmental processes, odontogenesis is highly complex and dynamically regulated, with hundreds of genes co-expressed in reciprocal networks. Tooth agenesis (missing one or more/all teeth) is a common human craniofacial anomaly and may be caused by genetic variations and/or environmental factors. Variants in PAX9, MSX1, AXIN2, EDA, EDAR, and WNT10A genes are associated with tooth agenesis. Currently, variants in ATF1, DUSP10, CASC8, IRF6, KDF1, GREM2, LTBP3, and components and regulators of WNT signaling WNT10B, LRP6, DKK, and KREMEN1 are at the forefront of interest. Due to the interconnectedness of the signaling pathways of carcinogenesis and odontogenesis, tooth agenesis could be a suitable marker for early detection of cancer predisposition. Variants in genes associated with tooth agenesis could serve as prognostic or therapeutic targets in cancer. This review aims to summarize existing knowledge of development and clinical genetics of teeth. Concurrently, the review proposes possible approaches for future research in this area, with particular attention to roles in monitoring, early diagnosis and therapy of tumors associated with defective tooth development.

• MeSH
• Anodontia epidemiology   genetics   MeSH
• Early Detection of Cancer MeSH
• Neoplastic Syndromes, Hereditary epidemiology   genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Association Studies MeSH
• Carcinogenesis MeSH
• Carcinoma epidemiology   genetics   MeSH
• Colorectal Neoplasms epidemiology   genetics   MeSH
• Humans MeSH
• Biomarkers, Tumor MeSH
• Ovarian Neoplasms epidemiology   genetics   MeSH
• Stomach Neoplasms epidemiology   genetics   MeSH
• Neoplasms epidemiology   genetics   MeSH
• Odontogenesis MeSH
• Wnt Signaling Pathway genetics   MeSH
• Signal Transduction genetics   MeSH
• MSX1 Transcription Factor genetics   MeSH
• PAX9 Transcription Factor genetics   MeSH
• Tooth Discoloration MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

BACKGROUND: In mammals, odontogenesis is regulated by transient signaling centers known as enamel knots (EKs), which drive the dental epithelium shaping. However, the developmental mechanisms contributing to formation of complex tooth shape in reptiles are not fully understood. Here, we aim to elucidate whether signaling organizers similar to EKs appear during reptilian odontogenesis and how enamel ridges are formed. RESULTS: Morphological structures resembling the mammalian EK were found during reptile odontogenesis. Similar to mammalian primary EKs, they exhibit the presence of apoptotic cells and no proliferating cells. Moreover, expression of mammalian EK-specific molecules (SHH, FGF4, and ST14) and GLI2-negative cells were found in reptilian EK-like areas. 3D analysis of the nucleus shape revealed distinct rearrangement of the cells associated with enamel groove formation. This process was associated with ultrastructural changes and lipid droplet accumulation in the cells directly above the forming ridge, accompanied by alteration of membranous molecule expression (Na/K-ATPase) and cytoskeletal rearrangement (F-actin). CONCLUSIONS: The final complex shape of reptilian teeth is orchestrated by a combination of changes in cell signaling, cell shape, and cell rearrangement. All these factors contribute to asymmetry in the inner enamel epithelium development, enamel deposition, ultimately leading to the formation of characteristic enamel ridges.

• MeSH
• Actins metabolism   MeSH
• Lipid Droplets metabolism   MeSH
• Odontogenesis physiology   MeSH
• Reptiles anatomy & histology   growth & development   metabolism   MeSH
• Microscopy, Electron, Transmission MeSH
• Gene Expression Regulation, Developmental physiology   MeSH
• Dental Enamel cytology   metabolism   ultrastructure   MeSH
• Tooth MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

During evolution, there has been a trend to reduce both the number of teeth and the location where they are found within the oral cavity. In mammals, the formation of teeth is restricted to a horseshoe band of odontogenic tissue, creating a single dental arch on the top and bottom of the jaw. Additional teeth and structures containing dental tissue, such as odontogenic tumors or cysts, can appear as pathologies. These tooth-like structures can be associated with the normal dentition, appearing within the dental arch, or in nondental areas. The etiology of these pathologies is not well elucidated. Reawakening of the potential to form teeth in different parts of the oral cavity could explain the origin of dental pathologies outside the dental arch, thus such pathologies are a consequence of our evolutionary history. In this review, we look at the changing pattern of tooth formation within the oral cavity during vertebrate evolution, the potential to form additional tooth-like structures in mammals, and discuss how this knowledge shapes our understanding of dental pathologies in humans.

• MeSH
• Biological Evolution * MeSH
• Humans MeSH
• Vertebrates growth & development   MeSH
• Odontogenesis * MeSH
• Mammals anatomy & histology   growth & development   MeSH
• Mouth growth & development   MeSH
• Tooth pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

The Eda pathway ( Eda, Edar, Edaradd) plays an important role in tooth development, determining tooth number, crown shape, and enamel formation. Here we show that the Eda pathway also plays a key role in root development. Edar (the receptor) is expressed in Hertwig's epithelial root sheath (HERS) during root development, with mutant mice showing a high incidence of taurodontism: large pulp chambers lacking or showing delayed bifurcation or trifurcation of the roots. The mouse upper second molars in the Eda pathway mutants show the highest incidence of taurodontism, this enhanced susceptibility being matched in human patients with mutations in EDA-A1. These taurodont teeth form due to defects in the direction of extension of the HERS from the crown, associated with a more extensive area of proliferation of the neighboring root mesenchyme. In those teeth where the angle at which the HERS extends from the crown is very wide and therefore more vertical, the mutant HERSs fail to reach toward the center of the tooth in the normal furcation region, and taurodont teeth are created. The phenotype is variable, however, with milder changes in angle and proliferation leading to normal or delayed furcation. This is the first analysis of the role of Eda in the root, showing a direct role for this pathway during postnatal mouse development, and it suggests that changes in proliferation and angle of HERS may underlie taurodontism in a range of syndromes.

• MeSH
• Tooth Abnormalities genetics   MeSH
• Child MeSH
• Ectodysplasins genetics   MeSH
• Phenotype MeSH
• Dental Pulp Cavity abnormalities   MeSH
• Humans MeSH
• Adolescent MeSH
• Molar abnormalities   embryology   MeSH
• Mice MeSH
• Odontogenesis genetics   MeSH
• X-Ray Microtomography MeSH
• Signal Transduction MeSH
• Tooth Root abnormalities   embryology   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH