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Biomedical subjects

Irma Thesleff

Publications and source records attributed to Irma Thesleff.

At least 37 records · Page 2Linked to original sources
PubMed2004

Follistatin regulates enamel patterning in mouse incisors by asymmetrically inhibiting BMP signaling and ameloblast differentiation.

Rodent incisors are covered by enamel only on their labial side. This asymmetric distribution of enamel is instrumental to making the cutting edge sharp. Enamel matrix is secreted by ameloblasts derived from dental epithelium. Here we show that overexpression of follistatin in the dental epithelium inhibits ameloblast differentiation in transgenic mouse incisors, whereas in follistatin knockout mice, ameloblasts differentiate ectopically on the lingual enamel-free surface. Consistent with this, in wild-type mice, follistatin was continuously expressed in the lingual dental epithelium but downregulated in the labial epithelium. Experiments on cultured tooth explants indicated that follistatin inhibits the ameloblast-inducing activity of BMP4 from the underlying mesenchymal odontoblasts and that follistatin expression is induced by activin from the surrounding dental follicle. Hence, ameloblast differentiation is regulated by antagonistic actions of BMP4 and activin A from two mesenchymal cell layers flanking the dental epithelium, and asymmetrically expressed follistatin regulates the labial-lingual patterning of enamel formation.

Ameloblasts↗
PubMed2004

Bono1: a gene associated with regions of deposition of bone and dentine.

We have examined the mRNA expression pattern of the murine expressed sequence tag (EST) clone in embryonic and early postnatal mice. Expression was strongly and specifically localised to developing bones and odontoblasts in teeth, therefore we have named this gene Bono1 (Bone and odontoblasts). Bono1, which has human, rat and chicken orthologues designated as FKSG28 was expressed in most ossification regions of the head including calvarial bones, skull and jaws. Expression was localised to osteoblasts derived from both intramembraneous and endochondral ossification processes. Comparative analysis of the expression of Bono1 in the mandible with Bone sialoprotein (BSP), a marker of advanced osteoblastogenesis, revealed that Bono1 expression starts later in the osteoblast cell lineage than BSP. In the tooth, Bono1 was localised in secretory odontoblasts. This expression was complementary to BSP, which was only present in early pre-odontoblasts. In secretory odontoblasts, Bono1 was shown to be co-expressed with Dentin sialophosphoprotein (DSPP). In summary, Bono1 was expressed in functional osteoblasts and odontoblasts and was associated with regions of matrix mineralization.

Animals↗
PubMed2004

Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate.

Classical research has suggested that early palate formation develops via epithelial-mesenchymal interactions, and in this study we reveal which signals control this process. Using Fgf10-/-, FGF receptor 2b-/- (Fgfr2b-/-), and Sonic hedgehog (Shh) mutant mice, which all exhibit cleft palate, we show that Shh is a downstream target of Fgf10/Fgfr2b signaling. Our results demonstrate that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by demonstrating that cell proliferation is decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b-/- mice. These results reveal a new role for Fgf signaling in mammalian palate development. We show that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an Fgf-Shh signaling network.

Animals↗
PubMed2004

Phenotypic changes in dentition of Runx2 homozygote-null mutant mice.

Genetic and molecular studies in humans and mice indicate that Runx2 (Cbfa1) is a critical transcriptional regulator of bone and tooth formation. Heterozygous mutations in Runx2 cause cleidocranial dysplasia (CCD), an inherited disorder in humans and mice characterized by skeletal defects, supernumerary teeth, and delayed eruption. Mice lacking the Runx2 gene die at birth and lack bone and tooth development. Our extended phenotypic studies of Runx2 mutants showed that developing teeth fail to advance beyond the bud stage and that mandibular molar organs were more severely affected than maxillary molar organs. Runx2 (-/-) tooth organs, when transplanted beneath the kidney capsules of nude mice, failed to progress in development. Tooth epithelial-mesenchymal recombinations using Runx2 (+/+) and (-/-) tissues indicate that the defect in mesenchyme cannot be rescued by normal dental epithelium. Finally, our molecular analyses showed differential effects of the absence of Runx2 on tooth extracellular matrix (ECM) gene expression. These data support the hypothesis that Runx2 is one of the key mesenchymal factors that influences tooth morphogenesis and the subsequent differentiation of ameloblasts and odontoblasts.

Animals↗
PubMed2003

Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot.

We have identified mouse and human cDNAs encoding a novel secreted BMP inhibitor, which we have named ectodin. It is most homologous (approximately 37% amino acid identity) to sclerostin that is a secreted BMP antagonist. Recombinant ectodin protein produced in cultured cells was efficiently secreted as a antagonist. Ectodin inhibited the activity of BMP2, BMP4, BMP6, and BMP7 for mouse preosteoblastic MC3T3-E1 cells, and bound to these BMPs with high affinity. Ectodin is intensely expressed in developing ectodermal organs, including teeth, vibrissae, and hair follicles. However, it is absent from the hair placodes and from the enamel knot signaling centers in teeth. In addition, several cell layers surrounding the enamel knots were completely devoid of ectodin transcripts. We analyzed the regulation and function of ectodin in tooth germs. Recombinant ectodin protein antagonized the BMP-mediated induction of Msx2 expression in cultured tooth explants, indicating that ectodin is a secreted BMP inhibitor. BMP2 and BMP7 stimulated ectodin expression in tooth explants, showing that it is part of a feedback mechanism controlling the activity of BMPs. The stimulation of ectodin expression by BMP was prevented by SHH and FGF4 but not by Wnt6. Hence, the feedback mechanism whereby BMPs upregulate their own inhibitor is counteracted by signals coexpressed with BMPs in the enamel knot. We conclude that ectodin is a novel BMP inhibitor which integrates BMP signaling with the SHH and FGF signal pathways and contributes in defining the exact spatiotemporal domain of BMP target field around the ectodermal signaling centers.

3T3 Cells↗
PubMed2003

Mechanisms of ectodermal organogenesis.

All ectodermal organs, e.g. hair, teeth, and many exocrine glands, originate from two adjacent tissue layers: the epithelium and the mesenchyme. Similar sequential and reciprocal interactions between the epithelium and mesenchyme regulate the early steps of development in all ectodermal organs. Generally, the mesenchyme provides the first instructive signal, which is followed by the formation of the epithelial placode, an early signaling center. The placode buds into or out of the mesenchyme, and subsequent proliferation, cell movements, and differentiation of the epithelium and mesenchyme contribute to morphogenesis. The molecular signals regulating organogenesis, such as molecules in the FGF, TGFbeta, Wnt, and hedgehog families, regulate the development of all ectodermal appendages repeatedly during advancing morphogenesis and differentiation. In addition, signaling by ectodysplasin, a recently identified member of the TNF family, and its receptor Edar is required for ectodermal organ development across vertebrate species. Here the current knowledge on the molecular regulation of the initiation, placode formation, and morphogenesis of ectodermal organs is discussed with emphasis on feathers, hair, and teeth.

Animals↗
PubMed2003

Progression of calvarial bone development requires Foxc1 regulation of Msx2 and Alx4.

Calvarial bones form by direct ossification of mesenchyme. This requires condensation of mesenchymal cells which then proliferate and differentiate into osteoblasts. Congenital hydrocephalus (ch) mutant mice lack the forkhead/winged helix transcription factor Foxc1. In ch mutant mice, calvarial bones remain rudimentary at the sites of initial osteogenic condensations. In this study, we have localized the ossification defect in ch mutants to the calvarial mesenchyme, which lacks the expression of transcription factors Msx2 and Alx4. This lack of expression is associated with a reduction in the proliferation of osteoprogenitor cells. We have previously shown that BMP induces Msx2 in calvarial mesenchyme (Development 125, 1241-1251, 1998). Here, we show that BMP also induces Alx4 in this tissue. We also show that BMP-induced expression of Msx2 and Alx4 requires Foxc1. We therefore suggest that Foxc1 regulates BMP-mediated osteoprogenitor proliferation and that this regulation is required for the progression of osteogenesis beyond the initial condensations in calvarial bone development.

Animals↗
PubMed2003

Stimulation of ectodermal organ development by Ectodysplasin-A1.

Organs developing as ectodermal appendages share similar early morphogenesis and molecular mechanisms. Ectodysplasin, a signaling molecule belonging to the tumor necrosis factor family, and its receptor Edar are required for normal development of several ectodermal organs in humans and mice. We have overexpressed two splice forms of ectodysplasin, Eda-A1 and Eda-A2, binding to Edar and another TNF receptor, Xedar, respectively, under the keratin 14 (K14) promoter in the ectoderm of transgenic mice. Eda-A2 overexpression did not cause a detectable phenotype. On the contrary, overexpression of Eda-A1 resulted in alterations in a variety of ectodermal organs, most notably in extra organs. Hair development was initiated continuously from E14 until birth, and in addition, the transgenic mice had supernumerary teeth and mammary glands, phenotypes not reported previously in transgenic mice. Also, hair composition and structure was abnormal, and the cycling of hairs was altered so that the growth phase (anagen) was prolonged. Both hairs and nails grew longer than normal. Molar teeth were of abnormal shape, and enamel formation was severely disturbed in incisors. Furthermore, sweat gland function was stimulated and sebaceous glands were enlarged. We conclude that ectodysplasin-Edar signaling has several roles in ectodermal organ development controlling their initiation, as well as morphogenesis and differentiation.

Animals↗
PubMed2003

Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity.

Sclerosteosis is a progressive sclerosing bone dysplasia. Sclerostin (the SOST gene) was originally identified as the sclerosteosis-causing gene. However, the physiological role of sclerostin remains to be elucidated. Sclerostin was intensely expressed in developing bones of mouse embryos. Punctuated expression of sclerostin was localized on the surfaces of both intramembranously forming skull bones and endochondrally forming long bones. Sclerostin-positive cells were identified as osteoclasts. Recombinant sclerostin protein produced in cultured cells was efficiently secreted as a monomer. We examined effects of sclerostin on the activity of BMP2, BMP4, BMP6, and BMP7 for mouse preosteoblastic MC3T3-E1 cells. Sclerostin inhibited the BMP6 and BMP7 activity but not the BMP2 and BMP4 activity. Sclerostin bound to BMP6 and BMP7 with high affinity but bound to BMP2 and BMP4 with lower affinity. In conclusion, sclerostin is a novel secreted osteoclast-derived BMP antagonist with unique ligand specificity. We suggest that sclerostin negatively regulates the formation of bone by repressing the differentiation and/or function of osteoblasts induced by BMPs. Since sclerostin expression is confined to the bone-resorbing osteoclast, it provides a mechanism whereby bone apposition is inhibited in the vicinity of resorption. Our findings indicate that sclerostin plays an important role in bone remodeling and links bone resorption and bone apposition.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Ectodysplasin, Edar and TNFRSF19 are expressed in complementary and overlapping patterns during mouse embryogenesis.

Ectodysplasin (Eda), a member of the tumor necrosis factor (TNF) superfamily, and its receptor Edar are necessary components of ectodermal organ development. Analysis of their expression patterns and mutant phenotypes has shown that during mouse hair and tooth development they may be involved in signalling between separate epithelial compartments. Here we have analysed ectodysplasin and Edar expression in other embryonic mouse tissues, and show that Edar mRNA is confined to the epithelium. Ectodysplasin and Edar are expressed in separate epithelial compartments in the developing brain and the lacrimal gland. In the salivary gland ectodysplasin is expressed in the mesenchyme and Edar in the epithelium. This is the first indication of ectodysplasin-Edar signalling between the epithelium and the mesenchyme. We also studied the expression pattern of a related TNF receptor, TNFRSF19, and show that it is expressed in an overlapping domain with Edar in the tooth, mammary gland, whiskers, and limb bud suggesting a potentially redundant role.

Amino Acid Sequence↗
PubMed2003

A missense mutation in PAX9 in a family with distinct phenotype of oligodontia.

Mutations in PAX9 have been described for families in which inherited oligodontia characteristically involves permanent molars. Our study analysed one large family with dominantly inherited oligodontia clinically and genetically. In addition to permanent molars, some teeth were congenitally missing in the premolar, canine, and incisor regions. Measurements of tooth size revealed the reduced size of the proband's and his father's deciduous and permanent teeth. This phenotype is distinct from oligodontia phenotypes associated with mutations in PAX9. Sequencing of the PAX9 gene revealed a missense mutation in the beginning of the paired domain of the molecule, an arginine-to-tryptophan amino-acid change occurring in a position absolutely conserved in all sequenced paired box genes. A mutation of the homologous arginine of PAX6 has been shown to affect the target DNA specificity of PAX6. We suggest that a similar mechanism explains these distinct oligodontia phenotypes.

Amino Acid Sequence↗
PubMed2003

Molecular mechanisms in calvarial bone and suture development, and their relation to craniosynostosis.

The development and growth of the skull is a co-ordinated process involving many different tissues that interact with each other to form a complex end result. When normal development is disrupted, debilitating pathological conditions, such as craniosynostosis (premature calvarial suture fusion) and cleidocranial dysplasia (delayed suture closure), can result. It is known that mutations in the fibroblast growth factor receptors 1, 2, and 3(FGFR1, 2, and 3), as well as the transcription factors MSX2 and TWIST cause craniosynostosis, and that mutations in the transcription factor RUNX2 (CBFA1) cause cleidocranial dysplasia. However, relatively little is known about the development of the calvaria: where and when these genes are active during normal calvarial development, how these genes may interact in the developing calvaria, and the disturbances that may occur to cause these disorders. In this work an attempt has been made to address some of these questions from a basic biological perspective. The expression patterns of the above-mentioned genes in the developing mouse skull are detailed. The microdissection and in vitro culture techniques have begun the task of identifying Fgfrs, Msx2, and Twist interacting in intricate signalling pathways that if disrupted could lead to craniosynostosis.

Animals↗
PubMed2003

Stem cells and tissue engineering: prospects for regenerating tissues in dental practice.

In general, human tissues have a very limited potential to regenerate. However, recent progress in stem cell research and in tissue engineering promises novel prospects for tissue regeneration in dental practice in the future. Stem cells have been discovered in many adult tissues, including teeth, and stem cells from embryos have the potential to form all adult tissues. Embryonic stem cells can now be cultured and even produced from adult cells by the nuclear transfer method. Due to the rapid progress of research in molecular biology, particularly in the field of developmental biology, we are now starting to understand at the level of genes and molecules how the development of dental tissues is regulated. For instance, specific signal molecules have been identified which regulate the development of teeth and bones from progenitor cells. This information is already being used for the generation of dentoalveolar tissues in vitro and in vivo. Could we perhaps grow new enamel, dentine, periodontal ligament, bone, or even whole new teeth for our patients in the future?

Bone Morphogenetic Proteins↗
PubMed2003

Root or crown: a developmental choice orchestrated by the differential regulation of the epithelial stem cell niche in the tooth of two rodent species.

The rodent incisor grows continuously throughout its lifetime. The epithelial stem cell niche is located at the apical end of the tooth and its progeny gives rise to the ameloblasts that form the hard enamel. Previously, mesenchymal FGF10 was shown to support the niche, in conjunction with epithelial Notch signaling. Here we show that in a different continuously growing tooth type, the molar of the sibling vole, a similar regulatory system is in place. Moreover, the identical expression pattern of Bmp4 compared to Fgf10 suggests that BMP4 could also be involved in the regulation of the epithelial stem cell niche. Notch and FGF10 signaling is mainly absent in the mouse molar, which stops growing and develops roots. The regulation of the epithelial stem cell niche seems to be flexible allowing for the existence of different tooth types, such as continuously growing teeth, and high and low crowned molars.

Animals↗
PubMed2003

Developmental biology and building a tooth.

During the last 15 years, we have started to understand tooth development at the gene level. The list of genes known to regulate the position, shape, or number of teeth is lengthening rapidly. Interestingly, so far all these genes have important functions in the mediation of cell communication, which is generally considered the most important mechanism driving embryonic development. The communication is mediated by small signal molecules that are sent to nearby cells, thereby affecting their behavior and advancing differentiation. There are dozens of different signals and their receptors and target genes, which together form complicated signaling networks. The defects in several human conditions affecting tooth development have been identified recently, and these genes have turned out to be necessary components of signaling networks. Experimental studies using transgenic mice as models for human syndromes such as ectodermal and cleidocranial dysplasia have pinpointed the exact roles of the disease genes and indicated ways for possible new therapies. It is also possible that by combining the knowledge of molecular regulation of tooth development with the recent breakthroughs in stem cell research, dreams of building new teeth in dental practice may come true in the future.

Animals↗
PubMed2002

Lunatic fringe, FGF, and BMP regulate the Notch pathway during epithelial morphogenesis of teeth.

Teeth develop as epithelial appendages, and their morphogenesis is regulated by epithelial-mesenchymal interactions and conserved signaling pathways common to many developmental processes. A key event during tooth morphogenesis is the transition from bud to cap stage when the epithelial bud is divided into specific compartments distinguished by morphology as well as gene expression patterns. The enamel knot, a signaling center, forms and regulates the shape and size of the tooth. Mesenchymal signals are necessary for epithelial patterning and for the formation and maintenance of the epithelial compartments. We studied the expression of Notch pathway molecules during the bud-to-cap stage transition of the developing mouse tooth. Lunatic fringe expression was restricted to the epithelium, where it formed a boundary flanking the enamel knot. The Lunatic fringe expression domains overlapped only partly with the expression of Notch1 and Notch2, which were coexpressed with Hes1. We examined the regulation of Lunatic fringe and Hes1 in cultured explants of dental epithelium. The expression of Lunatic fringe and Hes1 depended on mesenchymal signals and both were positively regulated by FGF-10. BMP-4 antagonized the stimulatory effect of FGF-10 on Lunatic fringe expression but had a synergistic effect with FGF-10 on Hes1 expression. Recombinant Lunatic fringe protein induced Hes1 expression in the dental epithelium, suggesting that Lunatic fringe can act also extracellularly. Lunatic fringe mutant mice did not reveal tooth abnormalities, and no changes were observed in the expression patterns of other Fringe genes. We conclude that Lunatic fringe may play a role in boundary formation of the enamel knot and that Notch-signaling in the dental epithelium is regulated by mesenchymal FGFs and BMP.

Animals↗
PubMed2002

Death receptor signaling giving life to ectodermal organs.

A new tumor necrosis factor (TNF) pathway has been identified that has an important function in the regulation of embryonic development. Three key components of this pathway are previously unknown proteins: the TNF ligand ectodysplasin (also known as EDA), its death domain-containing receptor EDAR, and the death domain adapter molecule EDARADD. This pathway was discovered and delineated through the cloning of genes that cause human hypohidrotic ectodermal dysplasia (HED) syndromes and by analysis of the corresponding mouse mutants (Tabby, downless, and crinkled) showing defects in hair, teeth, and several exocrine glands. EDAR signaling is mediated by the activation of nuclear factor kappa B, but other downstream targets are not known. Ectodysplasin-EDAR signaling mediates cell interactions within the ectoderm and regulates the initiation and morphogenesis of hair and teeth. It is also necessary for the development of fish scales, indicating that this pathway and its function have been conserved during the evolution of ectodermal organs.

Animals↗