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Biomedical subjects

I Thesleff

Publications and source records attributed to I Thesleff.

At least 55 records · Page 3Linked to original sources
PubMed1997

The Tabby phenotype is caused by mutation in a mouse homologue of the EDA gene that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains.

Mouse Tabby (Ta) and X chromosome-linked human EDA share the features of hypoplastic hair, teeth, and eccrine sweat glands. We have cloned the Ta gene and find it to be homologous to the EDA gene. The gene is altered in two Ta alleles with a point mutation or a deletion. The gene is expressed in developing teeth and epidermis; no expression is seen in corresponding tissues from Ta mice. Ta and EDA genes both encode alternatively spliced forms; novel exons now extend the 3' end of the EDA gene. All transcripts recovered have the same 5' exon. The longest Ta cDNA encodes a 391-residue transmembrane protein, ectodysplasin-A, containing 19 Gly-Xaa-Yaa repeats. The isoforms of ectodysplasin-A may correlate with differential roles during embryonic development.

Alternative Splicing↗
PubMed1997

Primary structure, developmental expression, and immunolocalization of the murine laminin alpha4 chain.

The complete primary structure of the mouse laminin alpha4 chain was derived from cDNA clones. The translation product contains a 24-residue signal peptide preceding the mature alpha4 chain of 1,792 residues. Northern analysis on whole mouse embryos revealed that the expression was weak at day 7, but it later increased and peaked at day 15. In adult tissues the strongest expression was observed in lung and cardiac and skeletal muscles. Weak expression was also seen in other adult tissues such as brain, spleen, liver, kidney, and testis. By in situ hybridization of fetal and newborn tissues, expression of the laminin alpha4 chain was mainly localized to mesenchymal cells. Strong expression was seen in the villi and submucosa of the developing intestine, the mesenchymal stroma surrounding the branching lung epithelia, and the external root sheath of vibrissae follicles, as well as in cardiac and skeletal muscle fibers. In the developing kidney, intense but transient expression was associated with the differentiation of epithelial kidney tubules from the nephrogenic mesenchyme. Immunohistologic staining with affinity-purified IgG localized the laminin alpha4 chain primarily to lung septa, heart, and skeletal muscle, capillaries, and perineurium.

Amino Acid Sequence↗
PubMed1997

Neurotrophin mRNA expression in the developing tooth suggests multiple roles in innervation and organogenesis.

To analyze the roles of neurotrophins during early development of rat teeth, we studied the expression of neurotrophin mRNAs from the initiation of first molar formation to the completion of crown morphogenesis. With RNAase protection assay all neurotrophin mRNAs were detected in embryonic teeth. In situ hybridization analysis revealed developmentally changing, distinct expression patterns for nerve growth factor (NGF) and neurotrophin-3 (NT-3), which were shown not to be regulated by or dependent on peripheral innervation. NGF mRNAs appeared in the mesenchymal target field of the tooth at the time of the trigeminal axon ingrowth (embryonic days 14-15: E14-E15), and they were also present along the pathway taken by growing trigeminal axons. NT-4/5 mRNAs were uniformly expressed in all epithelial cells, but brain-derived neurotrophic factor (BDNF) transcripts were not detected. All neurotrophins induced neurite outgrowth from E13-E16 trigeminal ganglion explants. These results suggest that NGF is involved in the guidance of trigeminal axons to embryonic teeth. In postnatal teeth, expression of NGF mRNAs, but not other neurotrophins, correlated with trigeminal axon ingrowth, proposing that NGF is involved in local sprouting and establishment of the final innervation pattern of the dental papilla and dentin. These results suggest that NGF is required for tooth innervation and that other neurotrophins may also have regulatory roles. In addition, the expression patterns of NGF, NT-3, and NT-4/5 as well as of neurotrophin receptors suggest that the neurotrophin system may also serve non-neuronal functions during tooth development.

Animals↗
PubMed1997

Expression patterns of bone morphogenetic proteins (Bmps) in the developing mouse tooth suggest roles in morphogenesis and cell differentiation.

Bone morphogenetic proteins (BMP) are secretory signal molecules which have a variety of regulatory functions during morphogenesis and cell differentiation. Teeth are typical examples of vertebrate organs in which development is controlled by sequential and reciprocal signaling between the epithelium and mesenchyme. In addition, tooth development is characterized by formation of mineralized tissues: the bone-like dentin and cementum as well as epithelially derived enamel. We have performed a comparative in situ hybridization analysis of the expression of six different Bmps (Bmp-2 to Bmp-7) starting from initiation of tooth development to completion of crown morphogenesis when dentine and enamel matrices are being deposited. Bmps-2, -4, and -7 were frequently codistributed and showed marked associations with epithelial-mesenchymal interactions. Their expression shifted between the epithelium and mesenchyme starting from the stage of tooth initiation. They were subsequently expressed in the enamel knot, the putative signaling center regulating tooth shape. Their expression domains prior to and during the differentiation of the dentine-forming odontoblasts and enamel-forming ameloblasts was in line with functions in regulation of cell differentiation and/or secretory activities of the cells. The expression of Bmp-3 was confined to mesenchymal cells, in particular to the dental follicle cells which give rise to the cementoblasts, forming the hard tissue covering the roots of teeth. Bmp-5 was expressed only in the epithelial ameloblasts. It was upregulated as the cells started to polarize and intense expression continued in the secretory ameloblasts. Bmp-6 was expressed only weakly in the dental mesenchyme during bud and cap stages. Our results are in line with regulatory functions of Bmps at all stages of tooth morphogenesis. Bmps-2, -4, and -7 are conceivably parts of signaling networks regulating tooth initiation and shape development. They as well as Bmp-5 may be involved in the induction and formation of dentine and enamel, and Bmp-3 in the development of cementum. The remarkable overlaps in the expression domains of different Bmp genes may implicate functional redundancy and/or formation of active heterodimers between different BMPs.

Animals↗
PubMed1997

Expression of GDNF and its receptors in developing tooth is developmentally regulated and suggests multiple roles in innervation and organogenesis.

Glial cell line-derived neurotrophic factor (GDNF) is a recently identified survival factor for several populations of neurons in the central and peripheral nervous system that also regulates kidney development. To study the roles of GDNF in the regulation of tooth innervation and formation, we analyzed by in situ hybridization the expression patterns of GDNF and its receptors Ret, GDNF family receptor alpha-1 (GFRalpha-1), and GFRalpha-2 from the initiation of first molar formation to the completion of crown morphogenesis. At the time of trigeminal axon ingrowth, GDNF mRNAs were expressed in the mesenchyme around the tooth germ (i.e., target field of the dental innervation), suggesting that it is involved in the regulation of the embryonic tooth innervation. This hypothesis was supported by the ability of GDNF to induce neurite outgrowth from embryonic day 12 (E12) to E15 trigeminal ganglia. This timing correlated with the appearance of Ret in the subset of cells in the trigeminal ganglion at E12, whereas GFRalpha-1 and GFRalpha-2 receptors were constantly expressed in trigeminal ganglion during E11-E15. After birth, GDNF expression showed apparent correlation with the ingrowth and presence of trigeminal nerve fibers in the tooth, suggesting that GDNF is involved in the regulation of innervation of the dental papilla and dentin postnatally. Ret, GFRalpha-1, and GFRalpha-2 mRNAs were expressed in the dental epithelial and mesenchymal cells at stages when epithelial-mesenchymal signalling regulates critical steps of tooth morphogenesis. Ret and GFRalpha-2 were colocalized in the dental mesenchyme during bud and cap stages. Expression of GFRalpha-1 associated with the formation of the epithelial enamel knot, which is a putative embryonic signalling center regulating tooth shape. During postnatal development, GDNF and its receptors were expressed in dental papilla mesenchyme. In addition, GDNF and GFRalpha-1 transcripts were seen in the preodontoblasts and odontoblasts, suggesting that they may be involved in differentiation and maintenance of functional properties of the odontoblasts. Taken together, these results suggest that GDNF acts as a target-derived neurotrophic factor during tooth innervation. In addition, GDNF and its receptors may have nonneuronal organogenetic functions during tooth morphogenesis.

Animals↗
PubMed1997

Signalling networks regulating dental development.

There has been rapid progress recently in the identification of signalling pathways regulating tooth development. It has become apparent that signalling networks involved in Drosophila development and development of mammalian organs such as the limb are also used in tooth development. Teeth are epithelial appendages formed in the oral region of vertebrates and their early developmental anatomy resembles that of other appendages, such as hairs and glands. The neural crest origin of tooth mesenchyme has been confirmed and recent evidence suggests that specific combinations of homeobox genes expressed in the neural crest cells may regulate the types of teeth and their patterning. Signalling molecules in the Shh, FGF, BMP and Wnt families appear to regulate the early steps of tooth morphogenesis and some transcription factors associated with these pathways have been shown to be necessary for tooth development. Several of the conserved signals are also transiently expressed in the enamel knots in the dental epithelium. The enamel knots are associated with the characteristic epithelial folding morphogenesis which is responsible for the development of tooth shape and it is currently believed that the enamel knots function as signalling centres regulating tooth shape development. The developing tooth has proven to be an excellent model in studies of the molecular basis of patterning and morphogenesis of organs and it can be expected that continuing studies will rapidly increase the understanding of these mechanisms.

Animals↗
PubMed1997

Detection of gelatinase B expression reveals osteoclastic bone resorption as a feature of early calvarial bone development.

Gelatinase B is a matrix metalloproteinase (MMP-9) produced by osteoclasts involved in bone resorption. Bone modeling, of which resorption is an integral part, is particularly evident in the intramembranous bones of the craniofacial region. To determine the role of osteoclasts in developing intramembranous bones we localized osteoclasts in calvariae from mice aged between embryonic day 16 and postnatal day 6, using gelatinase B and tartrate-resistant acid phosphatase activity (TRAP) as osteoclast markers. Through a combined approach of in situ hybridization and enzyme histochemistry, phenotypic differences between osteoclasts associated with calvarial bone were noted. Some cells expressed gelatinase B mRNA but were TRAP negative, whereas others demonstrated an overlap in enzyme profile exhibiting both TRAP activity and expressing gelatinase B mRNA. During more advanced development, most osteoclasts exhibited TRAP activity but did not express gelatinase B mRNA. The distribution of these cells differed, TRAP positive cells being detected in a widespread pattern at all ages, while gelatinase B transcripts were increasingly concentrated in areas of new and rapid bone growth, notably around the sutures. We propose the use of gelatinase B as an osteoclastic marker in the developing mouse. We conclude that gelatinase B may have a key role during early bone formation, the regulation of bone modeling, and perhaps in the maintenance of suture width.

Acid Phosphatase↗
PubMed1997

Localization of nerve cells in the developing rat tooth.

Earlier studies have shown that mammalian tooth formation can take place in the absence of peripheral nerve fibers. This has been taken to indicate that neurons are not needed for mammalian tooth development. However, our recent localization of peripherin, which is a neuronal cell marker, has suggested that neuronal cell bodies may be associated with developing teeth. In this study, we have analyzed in vivo and in vitro the presence of neuronal cells in developing rat tooth germs. When E14 and E16 rat first molars (thickening of presumptive dental epithelium and bud-stage tooth germ, respectively) were cultured in vitro, peripheral trigeminal axons degenerated. However, with antibodies against peripherin and L1 neural cell adhesion protein, we detected neuronal cell bodies and their axons in the explants. Next, the expression of neurofilament light-chain (NF-L) mRNAs was studied by in situ hybridization of embryonic E12 first branchial arches and tooth germs from initiation to completion of crown morphogenesis (E13, five-day post-natal teeth). NF-L transcripts were first seen at the bud stage (E15) next to the dental epithelium at the buccal side of the tooth germ. At the cap stage (E18), NF-L mRNAs were located under the oral epithelium at some distance from dental epithelium. These expression patterns correlate to the previous localization of peripherin-positive cells and suggest that NF-L expression also revealed neuronal cells. Taken together, these results demonstrate that, in addition to projections of peripheral neurons, neuronal cells are associated with the developing teeth. Hence, it is possible that neuronal cells may participate in the regulation of mammalian tooth formation.

Animals↗
PubMed1997

Mouse Serrate-1 (Jagged-1): expression in the developing tooth is regulated by epithelial-mesenchymal interactions and fibroblast growth factor-4.

Serrate-like genes encode transmembrane ligands to Notch receptors and control cell fate decisions during development. In this report, we analyse the regulation of the mouse Serrate-1 gene during embryogenesis. The Serrate-1 gene is expressed from embryonic day 7.5 (E7.5) and expression is often observed at sites of epithelial-mesenchymal interactions, including the developing tooth, where Serrate-1 is first (E11.5) expressed in all cells of the dental epithelium, but not in mesenchyme. A transient upregulation in dental mesenchyme (E12.5-15.5) is correlated with down-regulation of Serrate-1 expression in epithelial cells contacting the mesenchyme, i.e. in the cells destined to become ameloblasts. This expression pattern is reproduced in explants of dental epithelium and mesenchyme in vitro: epithelium induces Serrate-1 expression in mesenchyme, while epithelium in close proximity to this mesenchyme does not express detectable levels of Serrate-1 mRNA, suggesting that down-regulation of Serrate-1 expression in preameloblasts is caused by mesenchyme-derived signals. Finally, regulation of Serrate-1 expression differs from that of Notch genes. The Serrate-1 gene is induced in dental mesenchyme by fibroblast growth factor-4, but not by bone morphogenetic proteins, while the converse is true for Notch genes. This indicates that, at least during tooth development, the expression patterns observed for receptors and ligands in the Notch signaling pathway are generated by different induction mechanisms.

Animals↗
PubMed1997

Tooth morphogenesis and the differentiation of ameloblasts.

All vertebrate organs are formed from several cell types, and it is currently believed that interactions between the different components constitute the most important mechanism in the regulation of organ morphogenesis. In developing teeth morphogenetic interactions occur between the epithelium covering the facial processes and the underlying neural crest-derived mesenchyme. Morphogenesis is accompanied by differentiation of the various dental cell types, including the ameloblasts. Although ameloblasts differentiate terminally and start the deposition of enamel matrix only after the completion of crown morphogenesis, there is increasing evidence suggesting that the segregation of the ameloblast cell lineage may start much earlier. For example, the down-regulation of the North receptor, which in some other developmental system is associated with cell fate determination, is already seen in the dental epithelium prior to the bud stage. It is not known to what extent the differentiation of ameloblasts depends on tooth morphogenesis, and whether the same mesenchymal signals regulate morphogenesis and cell differentiation. There is evidence that growth factors act as morphogenetic signals. Bone morphogenetic proteins and fibroblast growth factors appear to regulate the initiation of tooth development, as well as the morphogenesis of the crown shape. However, the molecular nature of the signals regulating the advancing specialization of the cells in the ameloblast cell lineage remains unknown.

Ameloblasts↗
PubMed1996

Expression of neurotrophin receptors during rat tooth development is developmentally regulated, independent of innervation, and suggests functions in the regulation of morphogenesis and innervation.

Low-affinity neurotrophin receptor (LANR) and trk receptor tyrosine kinases (trks) serve as low- and high-affinity receptors for neurotrophins. Besides promoting the development and maintenance of the mammalian nervous system, it has been suggested that neurotrophins may have broader functions in the development of non-neuronal tissues. To evaluate the possible roles of neurotrophic factors in tooth development, we performed a detailed examination of the expression patterns of neurotrophin receptors during development of the rat tooth from initiation to completion of crown morphogenesis. mRNA expression was studied by in situ hybridisation and LANR protein was localised by immunohistochemistry. Furthermore, dissected tooth germs were cultured in vitro to examined the role of trigeminal innervation in the expression of neurotrophin receptors. mRNAs for LANR, trkB, and trkC, but not trkA, were detected in developing teeth. LANR and the truncated form of trkB, which lacks the intracellular tyrosine kinase domain, were expressed throughout tooth morphogenesis and their expression patterns were largely non-overlapping and changed spatio-temporally. trkC was expressed after birth, and it was restricted to dental papilla mesenchyme. The expression of all receptors correlated with the development of innervation, but, in addition, the expression of LANR and trkB appeared to be associated with cell differentiation and epithelial-mesenchymal interactions. The patterns of LANR, trkB, and trkC in teeth which underwent morphogenesis in organ culture were similar to those in vivo, which indicates that the expression of these neurotrophin receptors is not regulated by and does not depend on trigeminal innervation. The data suggest that neurotrophin receptors have roles in the development of tooth innervation, but that they also have non-neuronal, organogenetic functions.

Aging↗
PubMed1996

Molecular mechanisms of cell and tissue interactions during early tooth development.

BACKGROUND: Morphogenesis and cell differentiation during the development of all organs, including the tooth, are regulated by interactions between cells and tissues. The developing tooth is one of the organs in which the molecular mechanisms of such interactions are starting to be elucidated. RESULTS: Homotypic cell interactions take place between cells of the same developmental history, and they are a central mechanism in the formation of mesenchymal cell condensates during the bud stage of tooth development. Syndecan-1, a cell surface heparan sulfate proteoglycan, is transiently expressed in the dental mesenchyme and may regulate dental mesenchymal cell condensation. It binds tenascin, a matrix glycoprotein abundant in dental mesenchyme, suggesting involvement of cell-matrix interactions. Syndecan also binds growth factors, and its association with cell proliferation in the dental mesenchyme suggests roles in the regulation of cell number in the condensing cells. Inductive interactions between the epithelial and mesenchymal tissues regulate tooth development at all stages. In the early dental mesenchyme, the expression of several molecules, including syndecan and tenascin, are regulated by the epithelium. There is evidence that growth factors act as diffusible signals mediating these interactions. BMP-2 and BMP-4 (bone morphogenetic proteins), which belong to the TGF beta superfamily, are expressed in the early dental epithelium, and their effects on the dental mesenchyme mimic those of the epithelium. In particular, BMPs induce the expression of the homeobox-containing transcription factors Msx-1 and Msx-2 in the dental mesenchyme. CONCLUSIONS: Based on current knowledge about the molecular changes accompanying tooth development and the results of experimental studies, we present a model for molecular regulation of early tooth development.

Animals↗
PubMed1996

The enamel knot as a signaling center in the developing mouse tooth.

Mammalian tooth forms are produced during development by folding of the enamel epithelium but the molecular mechanisms involved in the formation and patterning of tooth cusps are not understood. We now report that several key signaling molecules found in well-known vertebrate signaling tissues such as the node, the notochord, the apical ectodermal ridge, and the zone of polarizing activity in the limb bud are specifically expressed in cells of the enamel knot, which is a transient cluster of dental epithelial cells. By comparing three-dimensional reconstructions of serial sections following in situ hybridization we localized Sonic hedgehog, Bone morphogenetic proteins-2, -4 and -7, as well as Fibroblast growth factor-4 in nested domains within the enamel knot. We suggest that the enamel knot acts as a signaling or organizing center, which provides positional information for tooth morphogenesis and regulates the growth of tooth cusps.

Animals↗
PubMed1996

Tooth morphogenesis and cell differentiation.

The tooth is one of the vertebrate organs in which development at the molecular level is beginning to be understood. Secreted signaling molecules have been identified that mediate sequential and reciprocal inductive interactions between the dental epithelium and mesenchyme. Transcription factors have been found that participate in these signaling cascades. A signaling or organizing center was recently discovered in the dental enamel knot that expresses the same signals as other organizing centers in the embryo, and which presumably regulates tooth shape. It has recently become evident that the signaling networks that operate in the development of mammalian teeth are similar to those that are involved in the development of other vertebrate organs.

Cell Differentiation↗
PubMed1996

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↗