Two genes for missing teeth.
Explore the source record for details and available documents.
Anodontia↗
Biomedical subjects
I Thesleff
Publications and source records attributed to I Thesleff.
Basal layer of epithelium expresses tenascin mRNA during healing of incisional skin wounds.
Tenascin is a large oligomeric glycoprotein of the extracellular matrix that is expressed prominently during embryonic development and wound healing. Previous studies on tenascin expression in wounds have used immunohistochemistry to describe the expression of tenascin in wounds. The present study used in situ hybridization to identify the cells expressing tenascin mRNA in healing wounds. The results demonstrate that the cells of the basal layer of epidermis, migrating over the healing wound, are expressing the mRNA for tenascin. Intense expression was seen during the first three days after wounding, but after seven days, after the epithelium had grown to cover the wound, no tenascin transcripts were seen in epithelial cells. The epithelial cells elsewhere in the skin were devoid of tenascin transcripts at all stages examined. Previously, prominent immunohistological staining for tenascin has been located in wounds below the migrating epithelial cells and it has been thought to be synthesized by stromal cells upon epithelial induction. Our findings in the present study indicate that tenascin is produced by epithelial cells, which apparently are induced to produce tenascin as they migrate after wounding.
Animals↗
Gene defect in hypodontia: exclusion of EGF, EGFR, and FGF-3 as candidate genes.
Hypodontia, congenital absence of one or a few permanent teeth without any systemic disorders, is regarded as an autosomally inherited dominant condition with varying expression and incomplete penetrance. Many studies have reported that the prevalence of hypodontia varies from 5% to 10% among European and Asian populations. The teeth most often missing are second premolars, upper lateral incisors, and lower central incisors. Consequently, we call this trait incisor-premolar hypodontia. Peg-shaped or strongly mesio-distally reduced upper lateral incisors demonstrate variation in the expression of the trait. The gene or genes causing incisorpremolar hypodontia are not known. We have begun the genetic mapping of hypodontia by using linkage analyses in seven Finnish three-generation families with 77 individuals, 31 affected with incisor-premolar hypodontia. As the first step, we studied the possibility of linkage between hypodontia and some candidate genes which have been suggested to have important functions during tooth development. Here we report the exclusion of EGF, EGFR, and FGF-3 loci as possible sites for gene mutation causing incisor-premolar hypodontia in our family material. Because of the close location of the FGF-3 and FGF-4 genes, the results also suggest the exclusion of the FGF-4 locus.
Adolescent↗
Apoptosis in the developing tooth: association with an embryonic signaling center and suppression by EGF and FGF-4.
Apoptosis was localized in developing mouse teeth from initiation of morphogenesis to completion of cusp formation by using modified TUNEL method for serial sections and Nile Blue staining for whole mounts. Apoptosis was first detected at bud stage (E12-E13) in the central cells of the invaginating dental epithelium suggesting involvement of cell death in epithelial budding morphogenesis. During cusp development, apoptotic cells were located in the enamel knots, which are transient clusters of dental epithelial cells proposed to act as signaling centers directing the morphogenesis of tooth cusps. Apoptosis was also detected in other restricted epithelial cell populations including the dental lamina, ameloblasts, as well as stratum intermedium and stellate reticulum cells suggesting that the removal of these epithelial cells occurs by apoptosis. Apoptotic cells, presumably osteoclasts, were also located on the surfaces of the developing alveolar bone. When dissected E13 dental epithelium or mesenchyme were cultured in isolation, apoptotic cells were abundant throughout the tissues, whereas when cultured together, apoptosis was inhibited in both tissues close to their interface indicating that epithelial-mesenchymal tissue interactions prevent apoptosis. Epidermal growth factor (EGF) and fibroblast growth factor-4 (FGF-4) inhibited apoptosis in the dental mesenchyme when applied locally using agarose or heparin-coated acrylic beads, suggesting involvement of these or related growth factors in the prevention of apoptosis in dental tissues in vivo. The spatially and temporally restricted distribution patterns of apoptotic cells suggest multiple roles for programmed cell death in dental development. Of particular interest is the removal of the enamel knots by apoptosis which may terminate their tasks as regulators of the patterning of the tooth cusps. The apical ectodermal ridge (AER) of the limb bud has similar signaling characteristics as the enamel knot, and it also undergoes apoptosis. Hence, apoptosis may be a general mechanism for the silencing of embryonic signaling centers.
Animals↗
Mouse Serrate-1 and Notch genes differ in their response to signaling molecules during odontogenesis.
Explore the source record for details and available documents.
Animals↗
Cloning of a novel bacteria-binding receptor structurally related to scavenger receptors and expressed in a subset of macrophages.
A novel murine plasma membrane protein has been identified in subpopulations of macrophages. It has an intracellular N-terminal domain, a transmembrane domain, and an extracellular region with a short spacer, an 89 Gly-Xaa-Yaa repeat-containing collagenous domain, and a C-terminal cysteine-rich domain. In situ hybridization and immunohistochemical staining have localized the protein to a subset of macrophages in the marginal zone of the spleen and the medullary cord of lymph nodes. No expression was observed in macrophages of liver or lung. Transfected COS cells synthesized a native trimeric plasma membrane protein that bound labeled bacteria and acetylated LDL, but not yeast or Ficoll. The results suggest that the novel protein is a macrophage-specific membrane receptor with a role in host defense, as it shows postnatal expression in macrophages, which are considered responsible for the binding of bacterial antigens and phagocytosis.
Amino Acid Sequence↗
92-kDa type IV collagenase and TIMP-3, but not 72-kDa type IV collagenase or TIMP-1 or TIMP-2, are highly expressed during mouse embryo implantation.
Expression of 72 kDa and 92 kDa type IV collagenases and the metalloproteinase inhibitors TIMPs 1, 2, and 3 was studied by in situ hybridization in implanting mouse embryos of days 5.5 to 7.5. The 92 kDa type IV collagenase was strongly expressed in invading trophoblasts, signals above background not being observed in the embryonic proper or placental tissue. In contrast, signals above background were not seen for the 72 kDa enzyme in any cells of the implantation region, including trophoblasts and stromal cells of the decidual tissue. Only cells in the mucosal stroma outside the decidual region displayed some expression. TIMP-3 was intensily expressed in maternal cells in the area surrounding the invading embryonic tissue. No expression was observed for TIMP-1 or TIMP-2 in the embryo proper, trophoblasts, or the area of the uterine decidual reaction. Weak signals appeared for TIMP-1 only in the circular layer of myometrial smooth muscle and in some uterine stroma cells distant from the site of embryo implantation. The results suggest a central role for 92 kDa type IV collagenase and TIMP-3 in the extracellular proteolysis associated with implantation of the early embryo.
Animals↗
Gene defect in hypodontia: exclusion of MSX1 and MSX2 as candidate genes.
Hypodontia, congenital lack of one or a few teeth, is an autosomally inherited dominant trait. Homeobox genes MSX1 and MSX2 are expressed in presumptive dental tissues at the stage of initiation of tooth development. Recently, tooth development was shown to be inhibited in transgenic mice lacking a functional Msx1 gene. Here, we studied the relationship of the MSX1 and MSX2 genes to familial hypodontia in five Finnish families with a total of 20 affected individuals, by linkage analysis. The pairwise lod-scores regarding the intragenic microsatellites in the MSX1 and MSX2 genes at a recombination fraction of 0.0 were -3.1 and -3.0, respectively, thus excluding these genes as causative loci for hypodontia in these families.
Anodontia↗
Midkine (MK), a heparin-binding growth/differentiation factor, is regulated by retinoic acid and epithelial-mesenchymal interactions in the developing mouse tooth, and affects cell proliferation and morphogenesis.
Midkine (MK) is the first cloned gene in a new family of heparin-binding growth/differentiation factors involved in the regulation of growth and differentiation. We have analyzed the expression of MK mRNA and protein during tooth development in mouse embryos and studied the regulation of MK expression and the biological effects of MK protein in organ cultures. MK expression was restricted and preferential in the tooth area as compared to the rest of the developing maxillary and mandibular processes suggesting specific functions for MK during tooth morphogenesis. MK mRNA and protein were expressed during all stages of tooth formation (initiation, morphogenesis, and cell differentiation), and shifts of expression were observed between the epithelial and mesenchymal tissue components. However, the expression of mRNA and protein showed marked differences at some stages suggesting paracrine functions for MK. Tissue recombination experiments showed that MK gene and protein expression are regulated by epithelial-mesenchymal interactions, and, moreover, that dental tissue induces the ectopic expression of MK protein in non-dental tissue. The expression of MK gene and protein in the mandibular arch mesenchyme from the tooth region were stimulated by local application of retinoic acid in beads. Cell proliferation was inhibited in dental mesenchyme around the beads releasing MK, but this effect was modulated by simultaneous application of FGF-2. Morphogenesis and cell differentiation were inhibited in tooth germs cultured in the presence of neutralizing antibodies for MK, whereas the development of other organs (e.g., salivary gland, kidney) was unaffected. These results suggest important roles for MK in the molecular cascade that regulates tooth development.
Animals↗
Expression of Notch 1, 2 and 3 is regulated by epithelial-mesenchymal interactions and retinoic acid in the developing mouse tooth and associated with determination of ameloblast cell fate.
Notch 1, Notch 2, and Notch 3 are three highly conserved mammalian homologues of the Drosophila Notch gene, which encodes a transmembrane protein important for various cell fate decisions during development. Little is yet known about regulation of mammalian Notch gene expression, and this issue has been addressed in the developing rodent tooth during normal morphogenesis and after experimental manipulation. Notch 1, 2, and 3 genes show distinct cell-type specific expression patterns. Most notably, Notch expression is absent in epithelial cells in close contact with mesenchyme, which may be important for acquisition of the ameloblast fate. This reveals a previously unknown prepatterning of dental epithelium at early stages, and suggests that mesenchyme negatively regulates Notch expression in epithelium. This hypothesis has been tested in homo- and heterotypic explant experiments in vitro. The data show that Notch expression is downregulated in dental epithelial cells juxtaposed to mesenchyme, indicating that dental epithelium needs a mesenchyme-derived signal in order to maintain the downregulation of Notch. Finally, Notch expression in dental mesenchyme is upregulated in a region surrounding beads soaked in retinoic acid (50-100 micrograms/ml) but not in fibroblast growth factor-2 (100-250 micrograms/ml). The response to retinoic acid was seen in explants of 11-12-d old mouse embryos but not in older embryos. These data suggest that Notch genes may be involved in mediating some of the biological effects of retinoic acid during normal development and after teratogenic exposure.
Ameloblasts↗
Tooth morphogenesis.
Explore the source record for details and available documents.
Cell Differentiation↗
Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis.
Midkine (MK) and heparin binding-growth associated molecule (HB-GAM or pleiotrophin), constitute a new family of heparin-binding proteins implicated in the regulation of growth and differentiation (T. Muramatsu (1993) Int. J. Dev. Biol. 37, 183-188). We used affinity-purified antibodies against MK and HB-GAM to analyze their distribution during mouse embryonic development. From 9 to 14.5 day post-coitum (dpc), both proteins were detected in central and peripheral nervous systems, facial processes, limb buds, sense organs, respiratory, digestive, urogenital, and skeletal systems. MK and HB-GAM were often localized on the surface of differentiating cells and in basement membranes of organs undergoing epithelial-mesenchymal interactions. The level of MK protein decreased considerably in the 16.5 dpc embryo, whereas HB-GAM staining persisted in many tissues. Our in situ hybridization results revealed a widespread expression of MK transcripts that was not always consistent with the distribution of MK protein in developing tissues. In many epithelio-mesenchymal organs MK and HB-GAM were codistributed with syndecan-1, a cell surface proteoglycan. In limb buds and facial processes, MK, HB-GAM, and syndecan-1 were localized to the apical epithelium and the adjacent proliferating mesenchyme. Both MK and HB-GAM bound syndecan-1 in solid-phase assays in a heparan sulfate-dependent manner. The biological effects of MK and HB-GAM on limb and facial mesenchyme were studied in vitro by application of beads preloaded with the proteins. Neither MK nor HB-GAM stimulated mesenchymal cell proliferation or induced syndecan-1 expression. Taken together these results indicate that MK and HB-GAM may play regulatory roles in differentiation and morphogenesis of the vertebrate embryo, particularly in epithelio-mesenchymal organs, and suggest molecular interactions with syndecan-1.
Animals↗
Homeobox genes and growth factors in regulation of craniofacial and tooth morphogenesis.
Homeobox genes encode a special group of transcription factors that regulate gene expression in the developing embryo. The so-called Hox-cluster genes were first discovered in the Drosophila (fruit fly). They specify the identity of body segments and their patterning along the anteroposterior axis. Other homeobox-containing genes appear to regulate patterning of the head and face. The function of the Msx-1 homeobox gene has been shown to be necessary for tooth development. In general, it is thought that special combinations of homeobox genes specify the patterning of individual structures. Bone morphogenetic proteins (BMPs) are growth factors belonging to the family of transforming growth factor-beta (TGF-beta). BMPs regulate bone and cartilage development, and individual BMPs have been shown to contribute to the shaping of various skeletal elements. BMPs regulate bone and dentin formation also postnatally, and they have therapeutic potential in reparative osteogenesis and odontogenesis. BMPs also act as inductive signals between tissue layers in the embryo, and they regulate the expression of several transcription factors, including homeobox-containing genes. BMP-4 has been identified as an epithelial inductive signal in tooth development. As it is produced by early dental epithelium and regulates tooth-specific gene expression in the dental mesenchyme, including Msx-1 expression, it may be an important signal for the initiation of tooth development.
Animals↗
Epithelial-mesenchymal signaling during tooth development.
Classic studies on experimental embryology have shown that organ development in an embryo is largely regulated by so called inductive tissue interactions which mostly take place between epithelial and mesenchymal tissues. Also in the developing tooth, both morphogenesis and cell differentiation are governed by such interactions. Characteristic features of epithelial-mesenchymal interactions are that they are sequential and reciprocal, i.e. "induction" appears to consist of a chain of signaling events between the tissues. During the last decade, the expression patterns of numerous molecules have been studied in developing organs by in situ hybridization and immunohistology. Many of them have been associated with epithelial-mesenchymal interactions, and it is apparent that same molecules participate in regulation of morphogenesis in a number of different organs. Transcription factors such as Msx-1, Msx-2 and Egr-1, growth factors, including TGF beta's, BMPs, and FGFs, and structural proteins such as syndecan and tenascin are expressed in transient, time and space-specific patterns in many organ rudiments, including the tooth. We have shown by tissue recombination studies that the expression of certain molecules is indeed regulated by epithelial-mesenchymal interactions in the early tooth germ. In particular, during the early stages of morphogenesis, when the dental epithelium induces the condensation of mesenchymal cells around the epithelial bud, the expression of many genes is upregulated in the condensed mesenchyme. Previous experimental tissue recombination studies have indicated that at the same time the capacity to instruct tooth morphogenesis shifts from the dental epithelium to the dental mesenchyme.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
EGF receptor expression in mineralized tissues: an in situ hybridization and immunocytochemical investigation in rat and human mandibles.
There is extensive evidence that growth factors play a central part in the autocrine/paracrine regulation of cell growth and differentiation in mineralized tissues. In order to investigate involvement of the EGFr receptor (EGFr) in forming mineralized tissues, its expression was studied by in situ hybridization and immunocytochemistry in mandibles of growing rats, as well as in human embryos. In Hertwig's epithelial root sheath of rat molar, EGFr mRNAs appeared strongly expressed, while dental pulp and dental follicle showed weak labeling. The lingual epithelium of rat incisor showed strong labeling, which decreased after epithelial dislocation. Cells of the adjoining lingual dental pulp and dental follicle, as compared to epithelium, contained a low level of EGFr mRNAs. In contrast, a significant signal with antisense RNA probe was observed in bone. Sense RNA probes provided a regular background or no labeling. Undifferentiated cells located in the periosteum and endosteal spaces were labeled. EGFr mRNAs were also present in osteoblasts and in lesser amounts in some osteocytes. In rat and in human bone, both osteoblasts and osteocytes were positive on immunostaining. Similarly in the Hertwig's root sheath, EGFr immunostaining and in situ hybridization labeling were closely related. These data show that different patterns of EGFr expression in forming mineralized tissues are tissue- and stage-specific. However, in all these cells, the present in situ investigation supports the assumption that EGFr is involved in the early stages of cellular proliferation and differentiation. This report also suggests that EGFr may play a role in differentiated and mature cells of mineralized tissues.
Animals↗
Comparison of expression of the msx-1, msx-2, BMP-2 and BMP-4 genes in the mouse upper diastemal and molar tooth primordia.
The existence of transient putative tooth anlagen in the prospective mouse upper diastema region has been documented previously in morphological studies. By in situ hybridization we investigated the expression patterns of the msx-1, msx-2, BMP-2 and BMP-4 genes, supposed to regulate early tooth development, in day 10-14 mouse embryonic upper diastema and molar regions, using 49 series of frontal sections. On the basis of comparison of the temporo-spatial expression patterns in both diastemal and molar tooth primordia we conclude that each of the four genes was expressed at least for some period simultaneously and at a comparable developmental stage in the transient and persisting dental primordia. BMP-2 and BMP-4 expression was downregulated in the diastemal dental primordia during their regression starting at day 13. The temporo-spatial pattern of BMPs expression may be associated with the disappearance of diastemal rudiments. Contrary to the molar anlage, we did not detect msx-2 gene expression in the diastemal dental rudiments after the stage of epithelial thickening. The deficiency of the msx-2 gene products may play a role in the growth retardation of diastemal dental primordia resulting in their subsequent involution.
Animals↗
Regulation of organogenesis. Common molecular mechanisms regulating the development of teeth and other organs.
Vertebrate organs develop from epithelial and mesenchymal tissues, and during their early development they share common morphological features. These include condensation of the mesenchymal cells and thickening, folding or branching of epithelial sheets. Sequential and reciprocal interactions between the epithelial and mesenchymal tissues play central roles in regulation of the morphogenesis of all organs. During recent years increasing amounts of molecular data have accumulated from studies describing developmental changes in expression patterns of molecules, as well as from functional in vitro studies and from the generation of transgenic mice. In this review article, we discuss common features in the molecular regulation that appear to be shared by the developing tooth and other organs. Several growth factors have been shown to act as inductive signals mediating epithelial-mesenchymal interactions in different organs. The early signals are proposed to regulate the expression of master regulatory genes, such as transcription factors. In early tooth germ, bone morphogenetic proteins BMP-2 and BMP-4 regulate expression of the homeobox containing genes Msx-1 and Msx-2. These may specify early patterning of organs through regulation of molecules at the cell surface and the extracellular matrix, such as syndecan-1 and tenascin. Changes in cell adhesion and matrix remodelling, particularly in the organ-specific mesenchyme and in basement membrane contribute to formation of mesenchymal cell condensations and to epithelial morphogenesis. Several growth factors and their receptors, particularly in the TGF beta-, FGF- and EGF- families, have been implicated in formation of mesenchymal condensates and in epithelial morphogenesis of many organs, including the tooth. It is apparent that molecules which regulate morphogenesis in different organs are potential candidate genes for congenital malformation syndromes in which several organs are affected.
Animals↗
Differential expression of the full-length and secreted truncated forms of EGF receptor during formation of dental tissues.
The developmental regulation of various receptor forms may be a key-element in the local fine tuning of growth factor effects. The present study focuses on the tissue- and stage-specificity of the alternative splicing of EGF receptor transcripts in the rat incisor. In situ hybridization, as well as light- and electron-microscopic immunolocalization were performed with a set of tools which enable us to discriminate the full-length and secreted truncated forms of EGF receptor. Our data show that, apart from a transient expression in differentiating odontoblasts, EGF receptor expression was predominantly observed in the dental epithelium. In the crown, the expression of the full-length EGF receptor was maximal during preameloblast proliferation and differentiation, decreased in differentiated ameloblasts, and remained low throughout enamel secretion. On the other hand, maturation stage ameloblasts, which regulate the final mineralization of enamel, express high levels of the full-length EGF receptor. In contrast with ameloblasts, epithelial supra-ameloblastic cells, which are not directly involved in the deposition of enamel matrix, showed an alternating predominance of the secreted truncated form during the secretion stage, and the full-length form during the maturation stage. The presence of the secreted truncated EGF receptor form was supported by the electron microscopic detection of extracellular aggregates of immunoreactive EGF receptor. Finally, Northern-blotting of enamel organ samples confirmed the presence of transcripts corresponding to mRNAs of both EGF receptor forms. During root formation, a decreasing gradient of full-length EGF receptor form expression was observed from the apical loop to the disrupting zone in root epithelium. The secreted truncated EGF receptor form was essentially detected in epithelial cells of the disrupting zone of root epithelium. During crown formation, the secreted truncated EGF receptor form, which appears to be synthesized by epithelial supra-ameloblastic cells and secreted toward ameloblasts, may competitively bind EGF receptor ligands and modify activation of the full-length EGF receptor.
Aging↗