Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.

• MeSH
• Ameloblasts metabolism   MeSH
• Amelogenesis Imperfecta * complications   immunology   MeSH
• Antigens immunology   metabolism   MeSH
• Polyendocrinopathies, Autoimmune * complications   immunology   MeSH
• Autoantibodies * immunology   MeSH
• Celiac Disease * complications   immunology   MeSH
• Immunoglobulin A immunology   MeSH
• Humans MeSH
• AIRE Protein deficiency   MeSH
• Proteins immunology   metabolism   MeSH
• Intestines immunology   metabolism   MeSH
• Dental Enamel immunology   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• AIRE protein, human MeSH Browser
• Antigens MeSH
• Autoantibodies * MeSH
• Immunoglobulin A MeSH
• AIRE Protein MeSH
• Proteins MeSH

Fluoride has toxic potential particularly for teeth, bones, and kidney. This study was aimed to investigate the NaF exposure effects on the growth of ameloblasts and kidney proximal tubular cells. Adult male healthy rats were used as experiment models, divided into control and NaF-induced groups. The expression of amelogenin, Bcl-2, and caspase-3 were significantly different in the control and NaF-induced group (P < 0.05). There was no correlation among these proteins in the control group but significant correlation in the NaF-induced group (r = 0.694). There was a significant correlation in proximal tubular cells, as seen from the increase of caspase-3 in the NaF-induced group (r = 0.715).

• MeSH
• Ameloblasts cytology   drug effects   metabolism   MeSH
• Epithelial Cells metabolism   MeSH
• Sodium Fluoride pharmacology   MeSH
• Immunohistochemistry MeSH
• Caspase 3 metabolism   MeSH
• Rats MeSH
• Cell Proliferation drug effects   MeSH
• Proto-Oncogene Proteins c-bcl-2 metabolism   MeSH
• Kidney Tubules, Proximal cytology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Sodium Fluoride MeSH
• Caspase 3 MeSH
• Proto-Oncogene Proteins c-bcl-2 MeSH

The continuously growing rodent incisor is an emerging model for the study of renewal of mineralized tissues by adult stem cells. Although the Bmp, Fgf, Shh, and Wnt pathways have been studied in this organ previously, relatively little is known about the role of Notch signaling during incisor renewal. Notch signaling components are expressed in enamel-forming ameloblasts and the underlying stratum intermedium (SI), which suggested distinct roles in incisor renewal and enamel mineralization. Here, we injected adult mice with inhibitory antibodies against several components of the Notch pathway. This blockade led to defects in the interaction between ameloblasts and the SI cells, which ultimately affected enamel formation. Furthermore, Notch signaling inhibition led to the downregulation of desmosome-specific proteins such as PERP and desmoplakin, consistent with the importance of desmosomes in the integrity of ameloblast-SI attachment and enamel formation. Together, our data demonstrate that Notch signaling is critical for proper enamel formation during incisor renewal, in part by regulating desmosome-specific components, and that the mouse incisor provides a model system to dissect Jag-Notch signaling mechanisms in the context of mineralized tissue renewal.

• Keywords
• AMELOBLAST, AMELOGENESIS, JAG, NOTCH, STRATUM INTERMEDIUM, TOOTH DEVELOPMENT,
• MeSH
• Ameloblasts metabolism   pathology   MeSH
• Desmosomes metabolism   pathology   MeSH
• Mice MeSH
• Tooth Diseases MeSH
• Receptors, Notch * MeSH
• Incisor metabolism   pathology   MeSH
• Signal Transduction * MeSH
• Dental Enamel metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Receptors, Notch * MeSH

In organized tissues, the precise geometry and the overall shape are critical for the specialized functions that the cells carry out. Odontoblasts are major matrix-producing cells of the tooth and have also been suggested to participate in sensory transmission. However, refined morphologic data on these important cells are limited, which hampers the analysis and understanding of their cellular functions. We took advantage of fluorescent color-coding genetic tracing to visualize and reconstruct in 3 dimensions single odontoblasts, pulp cells, and their assemblages. Our results show distinct structural features and compartments of odontoblasts at different stages of maturation, with regard to overall cellular shape, formation of the main process, orientation, and matrix deposition. We demonstrate previously unanticipated contacts between the processes of pulp cells and odontoblasts. All reported data are related to mouse incisor tooth. We also show that odontoblasts express TRPM5 and Piezo2 ion channels. Piezo2 is expressed ubiquitously, while TRPM5 is asymmetrically distributed with distinct localization to regions proximal to and within odontoblast processes.

• Keywords
• cell morphology, dentinogenesis, growth/development, protein expression, pulp biology, transgenic animals,
• MeSH
• Ameloblasts cytology   ultrastructure   MeSH
• Cell Nucleus ultrastructure   MeSH
• Cell Surface Extensions ultrastructure   MeSH
• Dentin ultrastructure   MeSH
• Extracellular Matrix ultrastructure   MeSH
• Fluorescent Antibody Technique MeSH
• Ion Channels ultrastructure   MeSH
• TRPM Cation Channels ultrastructure   MeSH
• Cell Compartmentation MeSH
• Mesenchymal Stem Cells cytology   ultrastructure   MeSH
• Microscopy, Electron, Scanning methods   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Odontoblasts cytology   ultrastructure   MeSH
• Incisor cytology   ultrastructure   MeSH
• Cell Shape MeSH
• Imaging, Three-Dimensional methods   MeSH
• Dental Pulp cytology   ultrastructure   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Ion Channels MeSH
• TRPM Cation Channels MeSH
• Piezo2 protein, mouse MeSH Browser
• Trpm5 protein, mouse MeSH Browser

Nuclear factor kappa B (NF-κB) signaling plays critical roles in many physiological and pathological processes, including regulating organogenesis. Down-regulation of NF-κB signaling during development results in hypohidrotic ectodermal dysplasia. The roles of NF-κB signaling in tooth development, however, are not fully understood. We examined mice overexpressing IKKβ, an essential component of the NF-κB pathway, under keratin 5 promoter (K5-Ikkβ). K5-Ikkβ mice showed supernumerary incisors whose formation was accompanied by up-regulation of canonical Wnt signaling. Apoptosis that is normally observed in wild-type incisor epithelium was reduced in K5-Ikkβ mice. The supernumerary incisors in K5-Ikkβ mice were found to phenocopy extra incisors in mice with mutations of Wnt inhibitor, Wise. Excess NF-κB activity thus induces an ectopic odontogenesis program that is usually suppressed under physiological conditions.

• Keywords
• Ikkβ, Wnt signaling, cervical loop, enamel, tooth development, wise,
• MeSH
• Adaptor Proteins, Signal Transducing MeSH
• Ameloblasts cytology   MeSH
• Amelogenin analysis   MeSH
• Apoptosis physiology   MeSH
• Epithelium embryology   MeSH
• Phenotype MeSH
• Keratin-15 genetics   MeSH
• I-kappa B Kinase physiology   MeSH
• Bone Morphogenetic Proteins genetics   MeSH
• Microradiography methods   MeSH
• Mutation genetics   MeSH
• Mice, Mutant Strains MeSH
• Mice MeSH
• NF-kappa B physiology   MeSH
• Odontogenesis physiology   MeSH
• Patched Receptors MeSH
• Promoter Regions, Genetic genetics   MeSH
• Hedgehog Proteins physiology   MeSH
• Receptors, Cell Surface physiology   MeSH
• X-Ray Microtomography methods   MeSH
• Incisor abnormalities   embryology   MeSH
• Wnt Signaling Pathway genetics   physiology   MeSH
• Imaging, Three-Dimensional methods   MeSH
• Dental Enamel cytology   MeSH
• Tooth Germ abnormalities   embryology   MeSH
• Tooth, Supernumerary etiology   genetics   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing MeSH
• Amelogenin MeSH
• Chuk protein, mouse MeSH Browser
• Keratin-15 MeSH
• I-kappa B Kinase MeSH
• Bone Morphogenetic Proteins MeSH
• Krt15 protein, mouse MeSH Browser
• NF-kappa B MeSH
• Patched Receptors MeSH
• Hedgehog Proteins MeSH
• Receptors, Cell Surface MeSH
• Shh protein, mouse MeSH Browser
• Sostdc1 protein, mouse MeSH Browser

Apoptosis during tooth development appears dependent on the apoptotic executioner caspase-3, but not caspase-7. Instead, activated caspase-7 has been found in differentiated odontoblasts and ameloblasts, where it does not correlate with apoptosis. To further investigate these findings, the mouse incisor was used as a model. Analysis of caspase-7-deficient mice revealed a significant thinner layer of hard tissue in the adult incisor. Micro computed tomography scan confirmed this decrease in mineralized tissues. These data strongly suggest that caspase-7 might be directly involved in functional cell differentiation and regulation of the mineralization of dental matrices.

• MeSH
• Ameloblasts cytology   enzymology   metabolism   MeSH
• Cell Differentiation * MeSH
• Time Factors MeSH
• Immunohistochemistry MeSH
• Caspase 7 genetics   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Odontoblasts cytology   enzymology   metabolism   MeSH
• Odontogenesis MeSH
• Cell Proliferation MeSH
• X-Ray Microtomography MeSH
• Incisor embryology   growth & development   metabolism   MeSH
• Dental Enamel embryology   growth & development   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Caspase 7 MeSH

The MYB family of transcription activators has been associated with a high proliferation rate and an undifferentiated state of cells in a number of tissues. Recently emerging data suggest that these molecules may also play a role in differentiation. In this study, the pattern of expression of c-MYB was followed during postnatal stages of mouse molar odontogenesis using immunohistochemistry on serial sections. Along with an abundance of the c-MYB protein in proliferating zones, we confirmed the presence of this protein in differentiated ameloblasts, odontoblasts, and osteoblasts. In addition, c-MYB was also found in cementoblasts and alveolar fibroblasts. These findings suggest integration of c-MYB into regulatory networks during hard-tissue differentiation and mineralization.

• MeSH
• Ameloblasts metabolism   MeSH
• Cell Differentiation genetics   MeSH
• Connective Tissue Cells metabolism   MeSH
• Genes, myc genetics   MeSH
• In Situ Nick-End Labeling MeSH
• Molar cytology   growth & development   metabolism   MeSH
• Mice MeSH
• Odontogenesis genetics   MeSH
• Alveolar Process cytology   growth & development   metabolism   MeSH
• Proto-Oncogene Proteins c-myb * analysis   genetics   metabolism   MeSH
• Bone Development genetics   physiology   MeSH
• Gene Expression Regulation, Developmental genetics   physiology   MeSH
• Dental Cementum metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Proto-Oncogene Proteins c-myb * MeSH

OBJECTIVES: The primary enamel knot (PEK) is a population of cells that shows spatio-temporal restricted apoptosis during tooth development. It has been shown that caspase-9 and Apaf-1 are essential for apoptosis in the PEK as well as the central caspase-3. Caspase-7, as another executioner member in the caspase machinery, is considered to have caspase-3 like properties. DESIGN: The aim of this study was to detect caspase-7 activation during molar tooth development with a special focus on the cells of the PEK and to correlate the expression with the pattern of apoptosis and caspase-3 activation. Apoptosis in the PEK was investigated in caspase-7 deficient mice to examine the functional consequence of loss of this specific caspase. In addition, odontoblasts and ameloblasts, which are known to undergo cell death during their secretory and maturation stages, were investigated. RESULTS: Cleaved caspase-7 was found in the apoptotic region of the PEK, however, caspase-7-deficient mice still possessed apoptotic cells in the PEK in a similar distribution to the wild type. Caspase-7 is therefore not essential for apoptosis in the PEK. Notably, cleaved caspase-7-positive cells were found at later stages in odontoblasts and ameloblasts, but expression did not correlate with apoptosis in these tissues. CONCLUSIONS: The results indicate a non-essential apoptotic role of caspase-7 in the PEK apoptosis but suggest also possible non-apoptotic functions for caspase-7 in tooth development.

• MeSH
• Ameloblasts cytology   MeSH
• Apoptosis physiology   MeSH
• Caspase 7 deficiency   genetics   metabolism   MeSH
• In Situ Nick-End Labeling MeSH
• Molar metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Odontoblasts cytology   MeSH
• Odontogenesis genetics   physiology   MeSH
• Tomography, X-Ray Computed MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Caspase 7 MeSH

The transcription factor c-Myb is involved in the control of cell proliferation, survival and differentiation. As these processes accompany the morphogenesis of developing teeth, this work investigates the possible role of c-Myb during odontogenesis. Analysis of the expression of c-Myb in the monophyodont mouse was followed by similar analysis in a diphyodont species, the pig, which has a dentition more closely resembling that of the human. The distribution of c-Myb was correlated with the pattern of proliferation and apoptosis and the tooth phenotype of c-Myb mutant mice was also assessed. In the mouse, c-Myb expression was detected throughout prenatal development of the first molar tooth. Negative temporospatial correlation was found between c-Myb expression and apoptosis, while c-Myb expression positively correlated with proliferation. c-Myb-positive cells, however, were more abundant than the proliferating cell nuclear antigen positive cells, suggesting other roles of c-Myb in odontogenesis. In the minipig, in contrast to the mouse, there was an asymmetrical arrangement of c-Myb positive cells, with a higher presence on the labial side of the tooth germ and dental lamina. A cluster of negative cells was situated in the mesenchyme close to the tooth bud. At later stages, the number of positive cells decreased and these cells were situated in the upper part of the dental papilla in the areas of future cusp formation. The expression of c-Myb in both species was strong in the odontoblasts and ameloblasts at the stage of dentin and enamel production suggesting a possible novel role of c-Myb during tooth mineralization.

• MeSH
• Alleles MeSH
• Ameloblasts cytology   metabolism   MeSH
• Apoptosis MeSH
• Dentition MeSH
• Species Specificity MeSH
• Embryo, Mammalian cytology   embryology   metabolism   MeSH
• Immunohistochemistry MeSH
• Cloning, Molecular MeSH
• In Situ Nick-End Labeling MeSH
• Swine, Miniature MeSH
• Mice MeSH
• Odontoblasts cytology   metabolism   MeSH
• Odontogenesis * MeSH
• Osteoclasts cytology   metabolism   MeSH
• Swine MeSH
• Cell Proliferation MeSH
• Proliferating Cell Nuclear Antigen metabolism   MeSH
• Cell Cycle Proteins genetics   metabolism   MeSH
• Proto-Oncogene Proteins c-myb genetics   metabolism   MeSH
• Trans-Activators genetics   metabolism   MeSH
• Gene Expression Regulation, Developmental MeSH
• Tooth cytology   embryology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Mybl2 protein, mouse MeSH Browser
• Proliferating Cell Nuclear Antigen MeSH
• Cell Cycle Proteins MeSH
• Proto-Oncogene Proteins c-myb MeSH
• Trans-Activators MeSH

The mouse incisor has two unusual features: it grows continuously and it is covered by enamel exclusively on the labial side. The continuous growth is driven in part by epithelial stem cells in the cervical loop region that can both self-renew and give rise to ameloblasts. We have previously reported that ectopic enamel is found on the lingual side of the incisor in mice with loss-of-function of sprouty (spry) genes. Spry2(+/-); Spry4(-/-) mice, in which three sprouty alleles have been inactivated, have ectopic enamel as a result of upregulation of epithelial-mesenchymal FGF signaling in the lingual part of the cervical loop. Interestingly, lingual enamel is also present in the early postnatal period in Spry4(-/-) mice, in which only two sprouty alleles have been inactivated, but ectopic enamel is not found in adults of this genotype. To explore the mechanisms underlying the disappearance of lingual enamel in Spry4(-/-) adults, we studied the fate of the lingual enamel in Spry4(-/-) mice by comparing the morphology and growth of their lower incisors with wild type and Spry2(+/-); Spry4(-/-) mice at several timepoints between the perinatal period and adulthood. Ameloblasts and enamel were detected on the lingual side in postnatal Spry2(+/-); Spry4(+/-) incisors. By contrast, new ectopic ameloblasts ceased to differentiate after postnatal day 3 in Spry4(-/-) incisors, which was followed by a progressive loss of lingual enamel. Both the posterior extent of lingual enamel and the time of its last deposition were variable early postnatally in Spry4(-/-) incisors, but in all Spry4(-/-) adult incisors the lingual enamel was ultimately lost through continuous growth and abrasion of the incisor.

• MeSH
• Adaptor Proteins, Signal Transducing MeSH
• Ameloblasts cytology   physiology   MeSH
• Embryonic Development MeSH
• Genotype MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• Membrane Proteins deficiency   genetics   MeSH
• Mice, Mutant Strains genetics   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Protein Serine-Threonine Kinases MeSH
• Nerve Tissue Proteins deficiency   MeSH
• Incisor growth & development   MeSH
• Mouth Mucosa cytology   physiology   MeSH
• Dental Enamel embryology   growth & development   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• Membrane Proteins MeSH
• Protein Serine-Threonine Kinases MeSH
• Nerve Tissue Proteins MeSH
• Spry2 protein, mouse MeSH Browser
• Spry4 protein, mouse MeSH Browser