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Mandibular first molars of mouse embryos were cultivated for examination of the effects of calcitonin (CT) and/or parathyroid hormone (PTH) on the odontogenesis of the molars, and for determination of whether and how CT, which is a PTH antagonist, has an influence on the effect of PTH on odontogenesis. On the second day, the inner enamel epithelium in the control group had already differentiated into pre-ameloblasts. Typical odontoblasts had secreted a layer of predentin. On the fourth day of culture, the pre-ameloblasts achieved terminal differentiation into secretory ameloblasts, and enamel and dentin had already been deposited. PTH (1 unit/mL) inhibited the odontogenesis of the cultured molars during the designated culture periods (two and four days), while CT (0.5 unit/mL) stimulated odontogenesis. On the second day, the development of the molars in the CT + PTH group showed an intermediate stage between the control and PTH-treated explants, but on day 4 it corresponded to that of the controls. Moreover, when the molars exposed to PTH for two days were untreated and treated with CT for an additional two days, the former produced a small quantity of enamel matrix, while the latter formed a large amount of the matrix. These histological findings were also supported by a morphometric analysis of the enamel matrix in the cultured molars. The present results suggest that CT stimulates, but PTH suppresses, the odontogenesis of the mouse embryonic molars, and that CT is an antagonist to the inhibitory effect of PTH on odontogenesis.
The golden Syrian hamster was selected to study molar odontogenesis. The development of the first molar was examined from the dental lamina stage through apposition. The dentition of the hamster follows the basic dental formula of the rodent. The morphology and chronology of the various stages of odontogenesis were studied and were compared to that of the gerbil, rat, and mouse. Observation of the initiation of odontogenesis at the dental lamina stage was noted on prenatal day 11. The bud stage was present on prenatal day 12, followed by the cap stage on prenatal day 13. The bell stage occurred on prenatal day 14 and 15, and the apposition stage was initiated on prenatal day 16. The process of odontogenesis in the hamster was recognized as typically rodent. Combined with the fact that the hamster is very docile in nature and an easy laboratory animal to handle, data from this investigation suggest that the hamster will continue to be a useful model in dental research.
Endogenous retinoids are present in the embryonic mouse mandible and reach a concentration peak immediately before the formation of the dental lamina. Because exogenous retinoids alter the pattern of the dental lamina and the expression of epidermal growth factor mRNA (a transcript necessary for initiation of odontogenesis), the role of retinoic acid in the initiation of odontogenesis was studied here. Citral (3,7-dimethyl-2,6-octadienal), a known inhibitor of retinoic acid synthesis, was used to block the endogenous synthesis of retinoic acid in the mouse embryonic mandible before the formation of the dental lamina (gestational day 9). A 24-h exposure to citral totally blocked tooth formation in 7/10 mandibles. Reductions of endogenous retinoic acid concentrations were confirmed by high-performance liquid chromatography. Tooth formation was restored by simultaneous treatment with all-trans retinoic acid or 9-cis retinoic acid during the citral exposures (first 24 h of culture). Endogenous retinoic acid is necessary for the initiation of odontogenesis.
The coordination of the activities of individual cells during development is regulated in part by epigenetic signals either encoded in the insoluble extracellular matrix or provided by small diffusible factors such as growth factors peptides and retinoids. Odontogenesis offers a suitable model to correlate the temporospatial distributions of such molecules, and of their cell receptors and ligands, with particular developmental processes. We have analyzed, by in situ hybridization, the distribution patterns of CRABPI, CRABPII and CRBPI transcripts during odontogenesis in the mouse. CRABPI transcripts were restricted to the mitogenic regions of the dental mesenchyme during late bell stages and were absent from post-mitotic odontoblasts. The only epithelial site of CRABPI transcription was the labial epithelial loop of the continuously growing incisor. CRABPII transcription was preponderant in the mitogenic zones of the dental epithelium: differential labeling of the dental epithelium occurred as early as the dental bud stage and during subsequent molar morphogenesis, this labeling became confined in the epithelial loops. The graded distribution of CRABPII transcripts along the anteroposterior axis of the continuously growing incisor was superimposed with the gradient of mitoses. CRABPII transcripts were absent from post-mitotic ameloblasts. It is concluded that during odontogenesis the expressions of the CRABPI and CRABPII genes are confined to regions exhibiting the highest rate of cell proliferation whenever differential mitotic activity is required. Moreover, the putative effects of retinoic acid on the regulation of cell proliferation kinetics in the dental epithelium and in the dental mesenchyme imply distinct CRABPs. CRBPI transcripts were restricted to the dental mesenchyme prior to the onset of CRABPI transcription. This observation supports the hypothesis that the two proteins might perform antagonistic functions in some retinoic acid-mediated developmental processes.
The enamel organ of the mammalian dental primordium undergoes a precise sequence of differentiation. To correlate this differentiation with tissue-specific markers we analysed the keratin protein composition and immunoreactivity of incisor primordia from the earliest stage of odontogenesis to the neonatal period. Throughout the enamel organ synthesized a characteristic subset of keratin proteins, and the expression of one specific keratin marked the onset of the cap stage. Interestingly, the immunoreactivity of the ameloblastic keratins against polyclonal antibodies increased with progressive odontogenesis, suggesting that cytokeratin filaments may undergo post-translational or conformational alterations during assembly within differentiating enamel-organ cells.
The initiation of odontogenesis depends on the site-specific proliferation of mandibular epithelium beginning at Day 11 in embryonic mice. We have previously reported that the local expression of epidermal growth factor mRNA in the murine mandible is developmentally regulated, expressed at Days 9 and 10 immediately prior to the initiation of tooth bud formation at Day 11. Exposure of Day 9 mandibular explants to antisense oligomers of epidermal growth factor blocks the initiation of odontogenesis. These results are the first demonstration of the involvement of epidermal growth factor in the inductive specification of a complex epithelial derivative.
The distribution of the cell adhesion molecule C-CAM was analyzed during tooth development, eruption and formation of the junctional epithelium in rat molars by immunohistochemistry and in situ hybridization. C-CAM could not be detected during odontogenesis until the late bell stage; then only the mRNA was demonstrated in the odontoblasts and ameloblasts. Prior to eruption, a local increase in C-CAM (mRNA and protein) was observed in the reduced enamel epithelium. During eruption, high C-CAM levels were seen in the fusion zone between the oral epithelium and the reduced enamel epithelium. In the adult rat, C-CAM remained strongly expressed in the junctional epithelium. Our study indicates that C-CAM may play a role in odontogenesis and during formation of the epithelial structures involved in tooth eruption and formation of the junctional epithelium.
Developing mammalian tooth is one of the most interesting model systems to study the mechanism of morphogenetic process especially to understand problems associated with spatial organization and symmetry. In the present article we recapitulate the morphologic aspects of odontogenesis and discuss the cellular and molecular regulatory factors involved in this process. The importance of cellular aspects such as epithelial-mesenchymal interactions and the cell kinetics are described. Role of growth factors such as Transferrin, Epidermal Growth Factor and its receptor and Transforming Growth Factor is analyzed. In addition the studies on transcription factors such as c-fos and Egr-1 and on homeobox genes are discussed to understand the molecular mechanism of odontogenesis.
Fetuses of pregnant CD-1 Swiss albino mice, exposed to 0.1% nicotine sulphate at a dose of 1.67 mg/kg body weight from the 6th to the 15th gestational day, were compared with control fetuses to assess the effects of nicotine on first molar odontogenesis. Mothers were sacrificed on the 18th day of gestation. The 130 nicotine treated fetuses, as well as the 348 control fetuses were embedded in paraffin and sectioned in the frontal plane. The developing molars of the experimental fetuses were retarded, less differentiated, and reduced in breadth in comparison with controls. The developing molars of the control fetuses were in the bell stage of odontogenesis, whereas those of the experimental population were either in the late cap or early cap stage, depending on the absence or presence of palatal cleft, which occurred in 9.6% of the fetuses. It is suggested that nicotine, or its metabolic byproducts, interfere with normal interaction between the epithelial and mesenchymal components of the developing tooth.
The developmental expression of retinoic acid (RA) nuclear receptors RAR(alpha, beta, gamma) and RXR(alpha, beta, gamma) was analysed during mouse odontogenesis by in situ hybridization on frozen sections and compared with the expression patterns of the cellular retinoic acid binding proteins CRABPI and II. The transcripts distribution of each RAR and RXR was basically similar in developing molars and incisors. RAR alpha and RXR alpha were preferentially expressed in dental epithelia, whereas RAR gamma and RXR gamma were transcribed in the dental mesenchyme. RAR beta, RAR gamma and RXR beta displayed both epithelial and mesenchymal expression. RAR beta expression was initiated during bell stage. RXR gamma transcripts were observed only at day 19.5 post coitum in the mitogenic mesenchyme facing the epithelial loops. Odontoblasts expressed RAR beta and RAR gamma, RXR alpha and RXR beta. Preameloblasts expressed RXR alpha and RXR beta and ameloblasts RXR gamma, RXR alpha and RXR beta. RAR alpha transcription in the incisor preameloblasts and ameloblasts was not observed in the first molar. The coexpression between RARs and RXRs might be important to form RAR/RXR heterodimers which are necessary to activate the transcriptions of target genes. CRABPI and CRABPII demonstrated graded variation of expression during odontogenesis in the mesenchyme and in the inner dental epithelium respectively. The pattern of CRABPI transcripts overlapped at least partially with expressions of all the studied nuclear receptors whereas CRABPII epithelial expression was superimposed with the transcription of RAR alpha, RXR alpha and RXR beta. These cytoplasmic proteins might participate in the storage and/or metabolism of RA and then distribute RA to colocalized nuclear receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
In this study we examined the possible inductive role of the dental papilla from polyphyodont lizard tooth germs. Flank skin sheets of quail ectoderm enzymatically separated from dermal tissue were recombined with lizard tooth papillae and placed on semisolid medium and cultured for 2 days. Subsequently, the recombinants were removed and placed on the chorioallantoic membrane of chick hosts and incubated for 6 days. After this period of 8 days in explant, control tissues differentiated according to their own phenotypes. Lizard dental papilla alone differentiated as fibroblasts. Quail flank skin ectoderm differentiated into epithelial sheets. Intact lizard tooth buds developed into teeth with dentine and incipient enamel. In the best experimental recombinants, advanced and relatively well-constructed teeth were observed, with clear indications of hard tissue deposition in association with quail epithelium. The results show that mesenchyme of the adult lizard dental papilla and embryonic quail ectoderm of heterotopic origin are capable of carrying out the complex sequence of morphogenetic interactions involved in normal odontogenesis.
Cyclophosphamide-induced changes in rodent odontogenesis were investigated by light and electron microscopy in four-day-old Sprague Dawley rats given one injection of 40 mg/kg of body weight of cyclophosphamide and killed at intervals of one hour, one day, one week and two weeks. Incisor and molar teeth were dissected from the animals, fixed in 2.0% glutaraldehyde in 0.1 M sodium cacodylate with 3.4% sucrose, and subsequently some were incubated for alkaline phosphatase reaction, and embedded in Spurr's medium for sectioning at light- and electron-microscopic levels. From three days a cell-sparse zone was created in the pulp in the growing end of the tooth and progressive cellular changes were observed which became more severe in the one-week and two-week specimens. Subodontoblast and adjacent pulpal cells were the most affected showing nuclear changes, damage to, or loss of, organelles, and inclusion bodies. Odontogenic epithelium was less affected and odontoblasts appeared to be unaffected by the drug. A new irregular matrix was laid down in the defect area and seemed to be the product of depolarized odontoblasts. This new matrix showed alkaline phosphatase activity, as did the cells embedded in it, and later it became mineralized. It is speculated that the polarity of odontoblasts might be maintained by an intact subodontoblastic layer; when this is lost the odontoblasts become depolarized and capable of secreting matrix from both ends.
The cytokeratin distribution in the developing rat enamel organ from day 15 of gestation through to 11 days post partum was examined immunohistochemically using a panel of monoclonal antibodies. A temporo-spatial programme of keratin expression was observed during odontogenesis and positive reactivity of the enamel organ was seen with the pan keratin antibodies CK1 (clone LP34 - reacts with a number of keratins including 6 and 18) and AE1-3 (reacts with most acidic and basic keratins). No reactivity was observed in the enamel organ with the other antibodies examined (Ks 8.12 [reacts with keratins 13 and 16], Ks 8.60 [reacts with keratins 10 and 11) and MCA157 [reacts with rat liver antigen]), although these antibodies did stain other epithelial tissues. This study supports the view that the epithelial cells of the enamel organ synthesize a tissue-specific subset of keratins which are related to the differentiation of the cells.
The ultrastructural localization and gradient of activity of alkaline phosphatase were studied with respect to cell differentiation, matrix synthesis, and matrix mineralization in the incisor and molar teeth of 4-day-old Sprague-Dawley rats. The animals were perfused intracardially at room temperature with 2.5% glutaraldehyde in 0.1M sodium cacodylate (pH 7.4) with 3-4% sucrose. The jaws were dissected, immersion-fixed for 24 h, and the incisor and molar tooth germs removed. These were determined in 10% EDTA in NaOH (pH 7.4) with 7% sucrose. After reactivation of the enzyme with 0.1M MgCl in Tris-maleate buffer (pH 7.4) at 4 degrees C, the medium consisting of 6 ml 3% sodium beta-glycerophosphate, 4 ml 0.2M Tris-HCl buffer (pH 9.2), 3 ml 1.6% MgSO4, 12 ml 0.5% lead citrate (pH congruent to 12), and 2.1 g sucrose. The pH was adjusted to 9.2 with 0.2M HCl, the volume made up to 30 ml, and the solution centrifuged for 10 min at 5000 rpm. Control teeth were incubated in medium minus the substrate. Finally, the specimens were routinely post-fixed and embedded for sectioning and examination with a Philips 300 electron microscopy. A gradient of alkaline phosphatase activity was mapped along the developing teeth in the cells of the stratum intermedium, the proximal borders of the ameloblasts, the early dentine matrix, the predentine-dentine border, matrix vesicles, and the plasma membranes of odontoblasts and subodontoblast cells. The gradient of alkaline phosphatase activity was evident in the forming tooth from the cervical loop to the crown apex and was related to the cellular events, matrix synthesis, and matrix mineralization occurring during odontogenesis.
Mandibular first molars of 17-day-old mouse embryos were cultured in vitro to examine the histological effects of various concentrations of parathyroid hormone (PTH) on odontogenesis of the molars. PTH did not affect the cytodifferentiation of mesenchymal cells into preodontoblasts but inhibited that of preodontoblasts into odontoblasts. Consequently, the odontoblasts failed to undergo dentinogenesis. On the other hand, inner enamel epithelium achieved terminal cytodifferentiation into secretory ameloblasts and these cells partially formed enamel in spite of the absence of dentin. All treated molars showed the same histological disturbances and these effects were independent of PTH dose. The present study indicated that PTH had an influence on mesenchyme-derived cells, inhibiting both the differentiation of odontoblasts and the formation of predentin and dentin.
To better characterize the molecular mechanism responsible for the bromodeoxyuridine (BrdU)-mediated arrest of mammalian odontogenesis in vitro, the nature of nuclear DNA-analogue interactions was determined. Bioactive doses of the radiolabelled analogue were added to tissue culture medium of 16-day old embryonic rat incisor primordia. Control rudiments were similarly exposed to equimolar, radiolabelled thymidine. After 16-18 h, DNA was isolated and purified from the labelled organ cultures. Following sedimentation to equilibrium through neutral CsCl density gradients, [3H]-BrdU-labelled DNA revealed a buoyant density indicative of a 12-15 per cent level of substitution in place of thymidine. Furthermore, similar centrifugation of DNA through alkaline density gradients suggested that the substitution was localized predominantly within a single-strand. DNA-DNA reassociation kinetics subsequently revealed that disproportionately more radiolabelled BrdU was concentrated within repetitive DNA nucleotide sequences in contrast to the more random distribution of [3H]-thymidine moieties. Thus it is likely that BrdU exerts its inhibitory effects on odontogenic differentiation through a relatively small proportion of rat embryo nuclear DNA.
Stocks used were male and female monozygotes for Robertsonian translocation specific for chromosomes 16 and 17 Rb(16.17)7Bnr and males and females homozygous for Robertsonian translocation for chromosomes 6 and 16 Rb(6.16)24Lub to produce double heterozygotes characterized as Rb(16.17)Bnr/Rb(6.16)24Lub. This study was based on 156 fetuses, of which 70 were normal (euploid/controls) and 86 were affected trisomics identified grossly by decreased size, shortened faces (flattened snouts), oedema, petechiae, open eyelids and dysplastic ears. Confirmation of trisomics included karyotyping metaphasic spreads. Throughout the five gestational days studied (14-18), trisomic fetuses exhibited developmental delays of up to 24 h. In general, tooth organs were smaller, hypocellular, hypoplastic and had a decreased blood supply. These differences were progressive and more pronounced in the later periods of odontogenesis, especially in the morpho- and histodifferentiation stages.