I Thesleff

..We propose that finely tuned antagonistic effects between follistatin and TGF beta superfamily signals are critical for enamel knot formation and function, as well as for patterning of tooth cusps...

..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...

..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...

..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?..

..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...

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..Necessary functions of many signals, receptors and transcription factors have been demonstrated in mice, and mutations causing dental defects in humans have been identified in several genes...

..In addition, subtle variations in this or in related regulatory networks may explain the different regenerative capacities of various organs and animal species...

..We suggest that the enamel knots are central regulators of tooth development, since they link cell differentiation to morphogenesis...

..Instead FGF-10 partially restored morphogenesis and stimulated the development of additional tooth cusps in cultured Tabby molars...

..This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways...

..We conclude that Runx2 mediates the functions of epithelial FGF signals regulating Fgf3 expression in the dental mesenchyme and that Fgf3 may be a direct target gene of Runx2...

..These results show that the life history of the enamel knot is intimately linked to the initiation of tooth shape development and support the role of the enamel knot as an embryonic signaling center...

..However, based on earlier tissue recombination experiments it is conceivable that the developmental arrest is determined by the early oral epithelium...

..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...

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..Signals from the dura mater may regulate the maintenance of sutural patency prenatally, whereas signals in the osteogenic fronts dominate after birth...

..In addition, although NTN appears not to be directly involved in the regulation of tooth morphogenesis, it may have non-neuronal, organogenetic functions during tooth formation...

..Similar buds were also present in Runx2 heterozygotes, and they may represent the extension of dental lamina for successional teeth. The results suggest that Runx2 prevents the formation of Shh-expressing buds for successional teeth...

..The coexpression of Fgfs with other signaling molecules including Shh and several Bmps and their partly similar effects suggest that the FGFs participate in the signaling networks during odontogenesis...

..We conclude that several splice forms are expressed during mouse tooth development, and that TGFbeta- and FGF-family growth factors may act as epithelial signals inducing tenascin expression in the dental mesenchyme...

..We propose a model of osteoblast differentiation integrating Twist and FGF in the same pathway, in which FGF acts both at early and late stages. Disruption of this pathway may lead to craniosynostosis...

..The developing tooth is one of the organs in which the molecular mechanisms of such interactions are starting to be elucidated...

..In addition, BMP-4 induced its own mesenchymal expression. These findings support the hypothesis that BMP-4 mediates epithelial-mesenchymal interactions during early tooth development...

..The dynamic expression patterns of different Fgfs in dental epithelium and mesenchyme and their interactions suggest existence of regulatory signaling cascades between epithelial and mesenchymal FGFs during tooth development...

..However, the molecular nature of the signals regulating the advancing specialization of the cells in the ameloblast cell lineage remains unknown...

..Based on these results, we suggest that the enamel knot may control tooth morphogenesis by concurrently stimulating cusp growth (via FGF-4 synthesis) and by directing folding of cusp slopes (by not proliferating itself)...

..g., salivary gland, kidney) was unaffected. These results suggest important roles for MK in the molecular cascade that regulates tooth development...

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..This together with differences in NF-kappaB responses suggests an explanation for the different mode of inheritance of the different downless alleles...

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..Finally, the intense expression of FGFR1 in odontoblasts and ameloblasts and FGFR2 IIIb in ameloblasts suggests that FGFs participate in regulation of their differentiation and/or secretory functions...

..We conclude that these conserved signalling molecules are associated with the initiation and early morphogenesis of the tongue papillae...

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..The remarkable overlaps in the expression domains of different Bmp genes may implicate functional redundancy and/or formation of active heterodimers between different BMPs...

..In conclusion, we suggest that Eda and Edar are associated with the onset of ectodermal patterning and that ectodysplasin/edar signaling also regulates the morphogenesis of hair follicles...

..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...

..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...

..The diversity of mammalian molar patterns may largely result from the heterotopic and iterative processes...

..Our findings provide genetic evidence that signaling by FGFR-2(IIIb) is critical for the morphological development of the inner ear...

..We conclude that the fate of the epithelium is regulated by external cues influenced by culture conditions, and that the molar has the intrinsic capacity to grow continuously...

..We conclude that expression of msx 1 in jaw mesenchyme requires a non-specific epithelial signal, whereas msx 2 expression in either epithelium or mesenchyme requires reciprocal interactions between specialized dental cell populations...

..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...

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..Our data suggest that BMPs are downstream of Wnt/beta-catenin and that their interplay may be a critical component in establishing correct patterning of hair follicles through the reaction-diffusion mechanism...

..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...

..Msx2 expression continued in the epithelial cell rests of Malassez, and the nearby cementoblasts intensely expressed Bmp3, which may regulate some functions of the fragmented epithelium...

..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...

..Spatiotemporal induction of the secondary enamel knots determines the cusp patterns of individual teeth and is likely to involve repeated activation and inhibition of signaling as suggested for patterning of other epithelial organs...

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..Ectodysplasin is the first TNF-like signaling molecule described known to be required for epithelial morphogenesis...

..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...

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..It can be speculated that the remarkable expression of tenascin in the dental mesenchymal cells as compared to other connective tissues is associated with their capacity to differentiate into hard-tissue-forming cells...

..We conclude that epithelial stem cells in the mouse incisors are not regulated directly by Wnt/beta-catenin signaling...

..Moreover, our data indicate that Shh is a likely transcriptional target of Edar, but, unlike noggin, recombinant Shh was unable to rescue primary hair placode formation in Eda-deficient skin explants...

..Taken together, our results suggest that Eda-A1 signalling promotes placodal cell fate during early development of ectodermal organs...

..Abbreviations: Bsp1, bone sialoprotein 1; GoPro49, Golgi protein 49 kDa; E16, embryonic day 16; HERS, Hertwig's epithelial root sheath; PDL, periodontal ligament; dpn, day post-natal...

..Thus, TGF-beta 1 RNA expression seems to be regulated by epithelial-mesenchymal interactions...

..Our results will allow mutation diagnostics in the majority of patients...

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..We conclude that incisor-premolar hypodontia is a genetic condition with autosomal-dominant transmission and that it is associated with several other dental abnormalities...

..Our findings indicate that Foxc1 integrates the Bmp and Fgf signalling pathways independently of Twist or Noggin. This signalling network is essential for the correct patterning and growth of calvarial bones...

..One of these presented with the only case of cleft palate among the patients. Our result confirms that haploinsufficiency for MSX1 serves as a mechanism that causes selective tooth agenesis but, alone, is not enough to cause oral clefts...

..These findings support the suggestions that tinkering with the signal pathways is the key mechanism underlying the morphological evolution of teeth as well as other organs...

..We also demonstrate that BMP2, BMP7 and FGF10 are potent inducers of p63 in cultured tissue explants. Hence, we suggest that p63 regulates the morphogenesis of surface ectoderm and its derivatives via multiple signalling pathways...

..Unlike Runx2, Runx3 was expressed in odontoblasts. However, Runx3 mutant mice did not show obvious tooth phenotype or deviations of Runx1 and Runx2 expression patterns in the tooth...

..Many targets of the growth factors have been identified, and mutations in several genes within the signaling networks cause defective tooth formation in both humans and mice...

..The pages also provide links to other biological databases on the Internet, both as context-dependent and as general links. We welcome submissions from researches elsewhere to include their information of gene expression and function...

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..The phenotype is presumably a consequence of haploinsufficiency of PAX9. In another Finnish family with molar tooth agenesis, we could not find similar sequence changes in PAX9...

..These may be associated with the exocytosis of glycosaminoglycan components into extracellular spaces and the formation of the stellate reticulum...

..In addition, tooth enamel formation is defective in a dose-dependent manner. We speculate that the tooth patterning defects are caused by ectopic Edar activity outside the signaling centers...

..Subtle variations in this or related regulatory networks may explain the different regenerative capacities of various organs and animal species...

..We conclude that ectodysplasin-Edar signaling has several roles in ectodermal organ development controlling their initiation, as well as morphogenesis and differentiation...

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..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...

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..Only cartilage formed in 4%, and both cartilage and bone formed in 4%. Our study confirms that calvarial mesenchyme, which normally gives rise to intramembranous bone, also has chondrogenic potential...

..Several pieces of evidence suggest Lrp4 as a Wnt inhibitor, as well. The finding that Eda-A1 induces placode inhibitors was unexpected, and underlines the importance of delicate fine-tuning of signalling during placode formation...

..Our results suggest that most aspects of tooth shape have the developmental potential for correlated changes during evolution which may, if not taken into account, obscure phylogenetic history...

..These results may implicate Wnt signaling in tooth renewal, a capacity that was all but lost when mammals evolved progressively more complicated tooth shapes...

..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...

..Fgfr4 transcripts were found in developing muscles. These data help to explain the disturbances in craniofacial growth exhibited by both patients and the growing number of transgenic mice carrying mutations in genes encoding FGFRs/Fgfrs...

..No wt-1 expression was detected at any stage of tooth development showing that wt-1 is not obligatory for regulation of Egr-1 expression...

..All these findings support the hypothesis that the diversity of tooth types and dental patterns may have resulted from tinkering with the conserved signal pathways, organized into complex networks, during evolution...

..Considering the role of mesenchyme in tooth induction and the design of tissue engineering protocols, our work may have uncovered how delicate control of tissue quantities alone influences the outcome between induction and inhibition...

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..Based on our findings we suggest that miRNAs modulate tooth morphogenesis largely by fine tuning conserved signaling networks and that miRNAs may have played important roles during tooth evolution...

..ERM, can be regulated independently from the regulation of stem cell maintenance. This developmental flexibility may underlie the developmental and evolutionary diversity in tooth patterning...

..In vitro experiments determined that Runx2 is a part of the FGF and BMP signaling pathways in tooth and bone development, respectively...

..This is the first time a Golgi membrane protein is shown to be expressed in a developmentally regulated manner during mesenchymal and cartilage development in mammals...

..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...

..TCDD interferes with tooth development by stimulating apoptosis in those cells of the dental epithelium, which are predetermined to undergo apoptosis during normal development...

..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...

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..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...

..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...

..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...