The Genetic Control of Early Tooth Development

1997 ◽  
Vol 8 (1) ◽  
pp. 4-39 ◽  
Author(s):  
R. Maas ◽  
M. Bei
Keyword(s):  
Tooth Development ◽  
Homeobox Gene ◽  
Experimental System ◽  
Tooth Germ ◽  
Tooth Formation ◽  
Tissue Interactions ◽  
Bmp4 Expression ◽  
Msx Genes ◽  
Deficient Mice

Most vertebrate organs begin their initial formation by a common, developmentally conserved pattern of inductive tissue interactions between two tissues. The developing tooth germ is a prototype for such inductive tissue interactions and provides a powerful experimental system for elucidation of the genetic pathways involved in organogenesis. Members of the Msx homeobox gene family are expressed at sites of epithelial-mesenchymal interaction during embryogenesis, including the tooth. The important role that Msx genes play in tooth development is exemplified by mice lacking Msx gene function. Msxldeficient mice exhibit an arrest in tooth development at the bud stage, while Msx2-deficient mice exhibit late defects in tooth development. The co-expression of Msx, Bmp, L ef1, and Activin βA genes and the coincidence of tooth phenotypes in the various knockout mice suggest that these genes reside within a common genetic pathway. Results summarized here indicate that Msx1 is required for the transmission of Bmp4 expression from dental epithelium to mesenchyme and also for L ef1 expression. In addition, we consider the role of other signaling molecules in the epithelial-mesenchymal interactions leading to tooth formation, the role that transcription factors such as Msx play in the propagation of inductive signals, and the role of extracellular matrix. Last, as a unifying mechanism to explain the disparate tooth phenotypes in Msxl- and Msx2-deficient mice, we propose that later steps in tooth morphogenesis molecularly resemble those in early tooth development.

Epithelial-mesenchymal interactions are required for msx 1 and msx 2 gene expression in the developing murine molar tooth

Development ◽  
1993 ◽  
Vol 117 (2) ◽  
pp. 461-470 ◽  
Author(s):  
A.K. Jowett ◽  
S. Vainio ◽  
M.W. Ferguson ◽  
P.T. Sharpe ◽  
I. Thesleff
Keyword(s):  
Gene Expression ◽  
Tooth Development ◽  
Homeobox Gene ◽  
Oral Epithelium ◽  
Tooth Formation ◽  
Dental Papilla ◽  
Tissue Interactions ◽  
Dental Epithelium

Duplication of the msh-like homeobox gene of Drosophila may be related to the evolution of the vertebrate head. The murine homologues of this gene, msx 1 and msx 2 are expressed in the developing craniofacial complex including the branchial arches, especially in regions of epithelial-mesenchymal organogenesis including the developing tooth. By performing in vitro recombination experiments using homochronic dental and non-dental epithelial and mesenchymal tissues from E10 to E18 mouse embryos, we have found that the maintenance of homeobox gene expression in the tooth is dependent upon tissue interactions. In homotypic recombinants, dental-type tissue interactions occur, leading to expression of both genes in a manner similar to that seen during in vivo development. msx 1 is expressed exclusively in mesenchyme, both in the dental papilla and follicle. msx 2 is expressed in the dental epithelium and only in the mesenchyme of the dental papilla. In heterotypic recombinants, the dental epithelium is able to induce msx 1 expression in non-dental mesenchyme, this potential being lost at the bell stage. In these recombinants msx 2 was induced by presumptive dental epithelium prior to the bud stage but not thereafter. The expression of msx 1 and msx 2 in dental mesenchyme requires the presence of epithelium until the early bell stage. However, whereas non-dental, oral epithelium is capable of maintaining expression of msx 1 in dental mesenchyme throughout tooth development, induction of msx 2 was temporally restricted suggesting regulation by a specific epithelial-mesenchymal interaction related to the inductive events of tooth formation. msx 1 and msx 2, as putative transcription factors, may play a role in regulating the expression of other genes during tooth formation. 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.

scholarly journals Expression, localization and synthesis of small leucine-rich proteoglycans in developing mouse molar tooth germ

2020 ◽  
Vol 64 (1) ◽  
Author(s):  
Angammana Randilini ◽  
Kaoru Fujikawa ◽  
Shunichi Shibata
Keyword(s):  
Organ Culture ◽  
Developmental Stages ◽  
Tooth Development ◽  
Expression Patterns ◽  
Tooth Germ ◽  
Molar Tooth ◽  
Cervical Region ◽  
Metabolic Labeling ◽  
Tooth Formation ◽  
Tooth Germs

The gene expression and protein synthesis of small leucine-rich proteoglycans (SLRPs), including decorin, biglycan, fibromodulin, and lumican, was analyzed in the context of the hypothesis that they are closely related to tooth formation. In situ hybridization, immunohistochemistry, and organ culture with metabolic labeling of [35S] were carried out in mouse first molar tooth germs of different developmental stages using ICR mice at embryonic day (E) 13.5 to postnatal day (P) 7.0. At the bud and cap stage, decorin mRNA was expressed only in the surrounding mesenchyme, but not within the tooth germ. Biglycan mRNA was then expressed in the condensing mesenchyme and the dental papilla of the tooth germ. At the apposition stage (late bell stage), both decorin and biglycan mRNA were expressed in odontoblasts, resulting in a switch of the pattern of expression within the different stages of odontoblast differentiation. Decorin mRNA was expressed earlier in newly differentiating odontoblasts than biglycan. With odontoblast maturation and dentin formation, decorin mRNA expression was diminished and localized to the newly differentiating odontoblasts at the cervical region. Simultaneously, biglycan mRNA took over and extended its expression throughout the new and mature odontoblasts. Both mRNAs were expressed in the dental pulp underlying the respective odontoblasts. At P7.0, both mRNAs were weakly expressed but maintained their spatial expression patterns. Immunostaining showed that biglycan was localized in the dental papillae and pulp. In addition, all four SLRPs showed clear immunostaining in predentin, although the expressions of fibromodulin and lumican mRNAs were not identified in the tooth germs examined. The organ culture data obtained supported the histological findings that biglycan is more predominant than decorin at the apposition stage. These results were used to identify biglycan as the principal molecule among the SLRPs investigated. Our findings indicate that decorin and biglycan show spatial and temporal differential expressions and play their own tissue-specific roles in tooth development.

Msx1 controls inductive signaling in mammalian tooth morphogenesis

Development ◽  
1996 ◽  
Vol 122 (10) ◽  
pp. 3035-3044 ◽  
Author(s):  
Y. Chen ◽  
M. Bei ◽  
I. Woo ◽  
I. Satokata ◽  
R. Maas
Keyword(s):  
Matrix Protein ◽  
Tooth Development ◽  
Molar Tooth ◽  
Extracellular Matrix Protein ◽  
Msx Genes ◽  
Tooth Morphogenesis ◽  
Tooth Germs ◽  
Vertebrate Organogenesis ◽  
Inductive Signaling

Members of the Msx homeobox family are thought to play important roles in inductive tissue interactions during vertebrate organogenesis, but their precise developmental function has been unclear. Mice deficient for Msx1 exhibit defects in craniofacial development and a failure of tooth morphogenesis, with an arrest in molar tooth development at the E13.5 bud stage. Because of its potential for experimental manipulation, the murine molar tooth germ provides a powerful system for studying the role of Msx genes in inductive signaling during organogenesis. To further analyze the role of Msx1 in regulating epithelial-mesenchymal interactions during tooth morphogenesis, we have examined the expression of several potential Msx1 downstream genes in Msx1 mutant tooth germs and we have performed functional experiments designed to order these genes into a pathway. Our results show that expression of Bone Morphogenetic Protein 4 (BMP4), the HMG box gene Lef1 and the heparan sulfate proteoglycan syndecan-1 is specifically reduced in Msx1 mutant dental mesenchyme, while expression of the extracellular matrix protein tenascin is unaffected. BMP4 soaked beads can induce Bmp4 and Lef1 expression in explanted wild-type dental mesenchymes, but only Lef1 expression in Msx1 mutant dental mesenchyme. We thus conclude that epithelial BMP4 induces its own expression in dental mesenchyme in a manner that requires Msx1. In turn, we show that addition of BMP4 to Msx1 deficient tooth germs bypasses the requirement for Msx1 and rescues epithelial development from the bud stage to the E14.5 cap stage. Lastly, we show that FGFs induce syndecan-1 expression in dental mesenchyme in a manner that also requires Msx-1. These results integrate Msx1 into a regulatory hierarchy in early tooth morphogenesis and demonstrate that Msx1 is not only expressed in dental mesenchyme in response to epithelial signals, but also in turn regulates the reciprocal expression of inductive signals in the mesenchyme which then act back upon the dental epithelium. We propose that Msx genes function repetitively during vertebrate organogenesis to permit inductive signaling to occur back and forth between tissue layers.

Cbfa1 is required for epithelial-mesenchymal interactions regulating tooth development in mice

Development ◽  
1999 ◽  
Vol 126 (13) ◽  
pp. 2911-2920 ◽  
Author(s):  
R.N. D'Souza ◽  
T. Aberg ◽  
J. Gaikwad ◽  
A. Cavender ◽  
M. Owen ◽  
...  
Keyword(s):  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Tooth Development ◽  
Enamel Organ ◽  
Molecular Characteristics ◽  
Cleidocranial Dysplasia ◽  
Autosomal Dominant Disorder ◽  
Tooth Formation ◽  
Dental Epithelium

Osteoblasts and odontoblasts, cells that are responsible for the formation of bone and dentin matrices respectively, share several molecular characteristics. Recently, Cbfa1 was shown to be a critical transcriptional regulator of osteoblast differentiation. Mutations in this gene cause cleidocranial dysplasia (CCD), an autosomal dominant disorder in humans and mice characterized by defective bone formation. CCD also results in dental defects that include supernumerary teeth and delayed eruption of permanent dentition. The dental abnormalities in CCD suggest an important role for this molecule in the formation of dentition. Here we describe results of studies aimed at understanding the functions of Cbfa1 in tooth formation. RT-PCR and in situ hybridization analyses show that Cbfa1 has a unique expression pattern in dental mesenchyme from the bud to early bell stages during active epithelial morphogenesis. Unlike that observed in osteoblast differentiation, Cbfa1 is downregulated in fully differentiated odontoblasts and is surprisingly expressed in ectodermally derived ameloblasts during the maturation phase of enamel formation. The role of Cbfa1 in tooth morphogenesis is further illustrated by the misshapen and severely hypoplastic tooth organs in Cbfa1−/− mice. These tooth organs lacked overt odontoblast and ameloblast differentiation and normal dentin and enamel matrices. Epithelial-mesenchymal recombinants demonstrate that dental epithelium regulates mesenchymal Cbfa1 expression during the bud and cap stages and that these effects are mimicked by the FGFs but not by the BMPs as shown by our bead implantation assays. We propose that Cbfa1 regulates the expression of molecules in mesenchyme that act reciprocally on dental epithelium to control its growth and differentiation. Taken together, our data indicate a non-redundant role for Cbfa1 in tooth development that may be distinct from that in bone formation. In odontogenesis, Cbfa1 is not involved in the early signaling networks regulating tooth initiation and early morphogenesis but regulates key epithelial-mesenchymal interactions that control advancing morphogenesis and histodifferentiation of the epithelial enamel organ.

scholarly journals Local application of Usag-1 siRNA can promote tooth regeneration in Runx2-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sayaka Mishima ◽  
Katsu Takahashi ◽  
Honoka Kiso ◽  
Akiko Murashima-Suginami ◽  
Yoshihito Tokita ◽  
...  
Keyword(s):  
Tooth Development ◽  
Local Application ◽  
Mouse Strains ◽  
Tooth Agenesis ◽  
Renal Capsule ◽  
Tooth Formation ◽  
Related Transcription Factor ◽  
Interfering Rna ◽  
Deficient Mice ◽  
Mouse Mandibles

AbstractRunt-related transcription factor 2 (Runx2)-deficient mice can be used to model congenital tooth agenesis in humans. Conversely, uterine sensitization-associated gene-1 (Usag-1)-deficient mice exhibit supernumerary tooth formation. Arrested tooth formation can be restored by crossing both knockout-mouse strains; however, it remains unclear whether topical inhibition of Usag-1 expression can enable the recovery of tooth formation in Runx2-deficient mice. Here, we tested whether inhibiting the topical expression of Usag-1 can reverse arrested tooth formation after Runx2 abrogation. The results showed that local application of Usag-1 Stealth small interfering RNA (siRNA) promoted tooth development following Runx2 siRNA-induced agenesis. Additionally, renal capsule transplantation of siRNA-loaded cationized, gelatin-treated mouse mandibles confirmed that cationized gelatin can serve as an effective drug-delivery system. We then performed renal capsule transplantation of wild-type and Runx2-knockout (KO) mouse mandibles, treated with Usag-1 siRNA, revealing that hindered tooth formation was rescued by Usag-1 knockdown. Furthermore, topically applied Usag-1 siRNA partially rescued arrested tooth development in Runx2-KO mice, demonstrating its potential for regenerating teeth in Runx2-deficient mice. Our findings have implications for developing topical treatments for congenital tooth agenesis.

Inhibition of Apoptosis in Early Tooth Development Alters Tooth Shape and Size

2006 ◽  
Vol 85 (6) ◽  
pp. 530-535 ◽  
Author(s):  
J.-Y. Kim ◽  
Y.-G. Cha ◽  
S.-W. Cho ◽  
E.-J. Kim ◽  
M.-J. Lee ◽  
...  
Keyword(s):  
Tooth Development ◽  
Tooth Germ ◽  
Dependent Manner ◽  
Crown Height ◽  
Concentration Dependent Manner ◽  
Molar Teeth ◽  
In Vitro Organ Culture ◽  
Shape And Size

Apoptosis plays important roles in various stages of organogenesis. In this study, we hypothesized that apoptosis would play an important role in tooth morphogenesis. We examined the role of apoptosis in early tooth development by using a caspase inhibitor, z-VAD-fmk, concomitant with in vitro organ culture and tooth germ transplantation into the kidney capsule. Inhibition of apoptosis at the early cap stage did not disrupt the cell proliferation level when compared with controls. However, the macroscopic morphology of mice molar teeth exhibited dramatic alterations after the inhibition of apoptosis. Crown height was reduced, and mesiodistal diameter was increased in a concentration-dependent manner with z-VAD-fmk treatment. Overall, apoptosis in the enamel knot would be necessary for the proper formation of molar teeth, including appropriate shape and size.

scholarly journals The Prx1 Homeobox Gene is Critical for Molar Tooth Morphogenesis

2006 ◽  
Vol 85 (10) ◽  
pp. 888-893 ◽  
Author(s):  
J.M. Mitchell ◽  
D.M. Hicklin ◽  
P.M. Doughty ◽  
J.H. Hicklin ◽  
J.W. Dickert ◽  
...  
Keyword(s):  
Tooth Development ◽  
Three Dimensional ◽  
Homeobox Gene ◽  
Molar Tooth ◽  
Mandibular Incisor ◽  
Mandibular Hypoplasia ◽  
Morphological Defects ◽  
Mandibular Region ◽  
Tooth Morphogenesis

The paired-related homeobox genes, Prx1 and Prx2, encode transcription factors critical for orofacial development. Prx1−/−/ Prx2−/− neonates have mandibular hypoplasia and malformed mandibular incisors. Although the mandibular incisor phenotype has been briefly described (ten Berge et al., 1998 , 2001 ; Lu et al., 1999 ), very little is known about the role of Prx proteins during tooth morphogenesis. Since the posterior mandibular region was relatively normal, we examined molar tooth development in Prx1−/−/ Prx2−/− embryos to determine whether the tooth malformation is primary to the loss of Prx protein or secondary to defects in surrounding tissues. Three-dimensional (3D) morphological reconstructions demonstrated that Prx1−/−/ Prx2−/− embryos had molar malformations, including cuspal changes and ectopic epithelial projections. Although we demonstrate that Prx1 protein is expressed only mesenchymally, 3D reconstructions showed important morphological defects in epithelial tissues at the cap and bell stages. Analysis of these data suggests that the Prx homeoproteins are critical for mesenchymal-epithelial signaling during tooth morphogenesis.

The role of effectors of the activin signalling pathway, activin receptors IIA and IIB, and Smad2, in patterning of tooth development

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4605-4613 ◽  
Author(s):  
Christine A. Ferguson ◽  
Abigail S. Tucker ◽  
Kristiina Heikinheimo ◽  
Masatoshi Nomura ◽  
Paul Oh ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Tooth Development ◽  
Homeobox Gene ◽  
Transforming Growth Factor Β ◽  
Signalling Pathway ◽  
Downstream Target ◽  
Maxillary Molars ◽  
Mandibular Molar ◽  
Tooth Germs

The gene for activin βA is expressed in the early odontogenic mesenchyme of all murine teeth but mutant mice show a patterning defect where incisors and mandibular molars fail to develop but maxillary molars develop normally. In order to understand why maxillary molar tooth development can proceed in the absence of activin, we have explored the role of mediators of activin signalling in tooth development. Analysis of tooth development in activin receptor II and Smad2 mutants shows that a similar tooth phenotype to activin βA mutants can be observed. In addition, we identify a novel downstream target of activin signalling, the Iroquois-related homeobox gene, Irx1, and show that its expression in activin βA mutant embryos is lost in all tooth germs, including the maxillary molars. These results strongly suggest that other transforming growth factor β molecules are not stimulating the activin signalling pathway in the absence of activin. This was confirmed by a non-genetic approach using exogenous soluble receptors to inhibit all activin signalling in tooth development, which reproduced the genetic phenotypes. Activin, thus, has an essential role in early development of incisor and mandibular molar teeth but this pathway is not required for development of maxillary molars.

The role of the msh homeobox gene during Drosophila neurogenesis: implication for the dorsoventral specification of the neuroectoderm

Development ◽  
1997 ◽  
Vol 124 (16) ◽  
pp. 3099-3109 ◽  
Author(s):  
T. Isshiki ◽  
M. Takeichi ◽  
A. Nose
Keyword(s):  
Cell Fate ◽  
Neural Development ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Loss Of Function ◽  
Spinal Cord Development ◽  
Dorsal Portion ◽  
Msx Genes

Development of the Drosophila central nervous system begins with the delamination of neural and glial precursors, called neuroblasts, from the neuroectoderm. An early and important step in the generation of neural diversity is the specification of individual neuroblasts according to their position. In this study, we describe the genetic analysis of the msh gene which is likely to play a role in this process. The msh/Msx genes are one of the most highly conserved families of homeobox genes. During vertebrate spinal cord development, Msx genes (Msx1-3) are regionally expressed in the dorsal portion of the developing neuroectoderm. Similarly in Drosophila, msh is expressed in two longitudinal bands that correspond to the dorsal half of the neuroectoderm, and subsequently in many dorsal neuroblasts and their progeny. We showed that Drosophila msh loss-of-function mutations led to cell fate alterations of neuroblasts formed in the dorsal aspect of the neuroectoderm, including a possible dorsal-to-ventral fate switch. Conversely, ectopic expression of msh in the entire neuroectoderm severely disrupted the proper development of the midline and ventral neuroblasts. The results provide the first in vivo evidence for the role of the msh/Msx genes in neural development, and support the notion that they may perform phylogenetically conserved functions in the dorsoventral patterning of the neuroectoderm.

BMP4 rescues a non-cell-autonomous function of Msx1 in tooth development

Development ◽  
2000 ◽  
Vol 127 (21) ◽  
pp. 4711-4718 ◽  
Author(s):  
M. Bei ◽  
K. Kratochwil ◽  
R.L. Maas
Keyword(s):  
Dental Pulp ◽  
Tooth Development ◽  
Survival Function ◽  
Tooth Germ ◽  
Tooth Formation ◽  
Kidney Capsule ◽  
Dependent Signal ◽  
Dental Epithelium ◽  
Tooth Germs

The development of many organs depends on sequential epithelial-mesenchymal interactions, and the developing tooth germ provides a powerful model for elucidating the nature of these inductive tissue interactions. In Msx1-deficient mice, tooth development arrests at the bud stage when Msx1 is required for the expression of Bmp4 and Fgf3 in the dental mesenchyme (Bei, M. and Maas, R. (1998) Development 125, 4325–4333). To define the tissue requirements for Msx1 function, we performed tissue recombinations between wild-type and Msx1 mutant dental epithelium and mesenchyme. We show that through the E14.5 cap stage of tooth development, Msx1 is required in the dental mesenchyme for tooth formation. After the cap stage, however, tooth development becomes Msx1 independent, although our experiments identify a further late function of Msx1 in odontoblast and dental pulp survival. These results suggest that prior to the cap stage, the dental epithelium receives an Msx1-dependent signal from the dental mesenchyme that is necessary for tooth formation. To further test this hypothesis, Msx1 mutant tooth germs were first cultured with either BMP4 or with various FGFs for two days in vitro and then grown under the kidney capsule of syngeneic mice to permit completion of organogenesis and terminal differentiation. Previously, using an in vitro culture system, we showed that BMP4 stimulated the growth of Msx1 mutant dental epithelium (Chen, Y., Bei, M. Woo, I., Satokata, I. and Maas, R. (1996). Development 122, 3035–3044). Using the more powerful kidney capsule grafting procedure, we now show that when added to explanted Msx1-deficient tooth germs prior to grafting, BMP4 rescues Msx1 mutant tooth germs all the way to definitive stages of enamel and dentin formation. Collectively, these results establish a transient functional requirement for Msx1 in the dental mesenchyme that is almost fully supplied by BMP4 alone, and not by FGFs. In addition, they formally prove the postulated downstream relationship of BMP4 with respect to Msx1, establish the non-cell-autonomous nature of Msx1 during odontogenesis, and disclose an additional late survival function for Msx1 in odontoblasts and dental pulp.

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