scholarly journals Sox2 Controls Periderm and Rugae Development to Inhibit Oral Adhesions

2020 ◽  
Vol 99 (12) ◽  
pp. 1397-1405
Author(s):  
Y.Y. Sweat ◽  
M. Sweat ◽  
W. Yu ◽  
M. Sanz-Navarro ◽  
L. Zhang ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Tooth Development ◽  
Conditional Knockout ◽  
Oral Epithelium ◽  
Palatal Shelf ◽  
Palatal Rugae ◽  
Dental Epithelium ◽  
Incisor Development ◽  
Periderm Formation ◽  
Transient Structure

In humans, ankyloglossia and cleft palate are common congenital craniofacial anomalies, and these are regulated by a complex gene regulatory network. Understanding the genetic underpinnings of ankyloglossia and cleft palate will be an important step toward rational treatment of these complex anomalies. We inactivated the Sry (sex-determining region Y)–box 2 ( Sox2) gene in the developing oral epithelium, including the periderm, a transient structure that prevents abnormal oral adhesions during development. This resulted in ankyloglossia and cleft palate with 100% penetrance in embryos examined after embryonic day 14.5. In Sox2 conditional knockout embryos, the oral epithelium failed to differentiate, as demonstrated by the lack of keratin 6, a marker of the periderm. Further examination revealed that the adhesion of the tongue and mandible expressed the epithelial markers E-Cad and P63. The expanded epithelia are Sox9-, Pitx2-, and Tbx1-positive cells, which are markers of the dental epithelium; thus, the dental epithelium contributes to the development of oral adhesions. Furthermore, we found that Sox2 is required for palatal shelf extension, as well as for the formation of palatal rugae, which are signaling centers that regulate palatogenesis. In conclusion, the deletion of Sox2 in oral epithelium disrupts palatal shelf extension, palatal rugae formation, tooth development, and periderm formation. The periderm is required to inhibit oral adhesions and ankyloglossia, which is regulated by Sox2. In addition, oral adhesions occur through an expanded dental epithelial layer that inhibits epithelial invagination and incisor development. This process may contribute to dental anomalies due to ankyloglossia.

Wnt Production in Dental Epithelium Is Crucial for Tooth Differentiation

2019 ◽  
Vol 98 (5) ◽  
pp. 580-588 ◽  
Author(s):  
Y. Xiong ◽  
Y. Fang ◽  
Y. Qian ◽  
Y. Liu ◽  
X. Yang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Tooth Development ◽  
Wnt Signaling Pathway ◽  
Conditional Knockout ◽  
Canonical Wnt Signaling ◽  
Odontoblast Differentiation ◽  
Wnt Ligands ◽  
Dental Epithelium ◽  
Canonical Wnt

The Wnt ligands display varied spatiotemporal expression in the epithelium and mesenchyme in the developing tooth. Thus far, the actions of these differentially expressed Wnt ligands on tooth development are not clear. Shh expression specifies the odontogenic epithelium during initiation and is consistently restricted to the dental epithelium during tooth development. In this study, we inactivate Wntless ( Wls), the key regulator for Wnt trafficking, by Shh-Cre to investigate how the Wnt ligands produced in the dental epithelium lineage act on tooth development. We find that conditional knockout of Wls by Shh-Cre leads to defective ameloblast and odontoblast differentiation. WlsShh-Cre teeth display reduced canonical Wnt signaling activity in the inner enamel epithelium and the underlying mesenchyme at the early bell stage, as exhibited by target gene expression and BAT-gal staining. The expression of Wnt5a and Wnt10b is not changed in WlsShh-Cre teeth. By contrast, Wnt10a expression is significantly increased in response to epithelial Wls deficiency. In addition, the expression of Hedgehog signaling pathway components Shh, Gli1, and Patched1 was greatly decreased in WlsShh-Cre teeth. Epithelial Wls loss of function in Shh lineage also leads to aberrant cell proliferation in dental epithelium and mesenchyme at embryonic day 16.5; however, the cell apoptosis is unaffected. Moreover, we find that Decorin and Col1a1, the key markers for odontoblast differentiation that are downregulated in WlsShh-Cre teeth, act as direct downstream targets of the canonical Wnt signaling pathway by chromatin immunoprecipitation analysis. Additionally, Decorin and Col1a1 expression can be increased by lithium chloride (LiCl) treatment in the in vitro tooth explants. Taken together, our results suggest that the spatial expression of Wnt ligands within the dental epithelial lineage regulates the differentiation of tooth structures in later stages.

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.

Associations between transforming growth factor beta 1 RNA expression and epithelial-mesenchymal interactions during tooth morphogenesis

Development ◽  
1991 ◽  
Vol 113 (3) ◽  
pp. 985-994 ◽  
Author(s):  
A. Vaahtokari ◽  
S. Vainio ◽  
I. Thesleff
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tooth Development ◽  
Brdu Incorporation ◽  
Oral Epithelium ◽  
Rna Expression ◽  
Tgf Beta ◽  
Growth Factor Beta ◽  
Dental Epithelium

We have studied the expression of transforming growth factor beta-1 (TGF-beta 1) RNA during mouse tooth development, using in situ hybridization and experimental tissue recombinations. Analysis of the serial sections revealed the appearance of local expression of TGF-beta 1 RNA in the dental epithelium at bud-staged teeth (13-day embryos). Just before transition to the cap stage, TGF-beta 1 RNA expression rapidly increased in the epithelial bud, and it also extended to the condensed dental mesenchyme. At cap stage (14- and 15-day embryos), there was an intense expression of TGF-beta 1 RNA in the morphologically active cervical loops of the dental epithelium. During early bell stage (16- and 17-day embryos), TGF-beta 1 RNA expression was detected in the inner enamel epithelium where it subsequently almost disappeared (18-day embryos). After birth TGF-beta 1 transcripts transiently appeared in these cells when they were differentiating into ameloblasts (1-day mice). The transcripts were lost from the ameloblasts when they became secretory (4-day mice), but the expression continued in ameloblasts in enamel-free areas. Transient expression of TGF-beta 1 RNA was also detected in epithelial stratum intermedium cells at the time of ameloblast differentiation. In the mesenchyme, TGF-beta 1 RNA was not detected during bell stage until it appeared in differentiated odontoblasts (18-day embryos). The secretory odontoblasts continued to express TGF-beta 1 RNA at all stages studied including the odontoblasts of incisor roots. Analysis of the distribution of bromodeoxyuridine (BrdU) incorporation indicated apparent correlations between TGF-beta 1 RNA expression and cell proliferation at the bud and cap stages but not at later stages of tooth development. Tissue recombination experiments of bud-staged (13-day embryos) dental and non-dental tissues showed that tooth epithelium, when cultured together with tooth mesenchyme, expressed TGF-beta 1 RNA. When the tooth epithelium was combined with non-dental jaw mesenchyme, TGF-beta 1 transcripts were not expressed. However, TGF-beta 1 RNA expression was seen in oral epithelium cultured with dental mesenchyme, while no expression of TGF-beta 1 transcripts was seen in the oral epithelium during normal development. Thus, TGF-beta 1 RNA expression seems to be regulated by epithelial-mesenchymal interactions.

Sonic hedgehog regulates growth and morphogenesis of the tooth

Development ◽  
2000 ◽  
Vol 127 (22) ◽  
pp. 4775-4785 ◽  
Author(s):  
H.R. Dassule ◽  
P. Lewis ◽  
M. Bei ◽  
R. Maas ◽  
A.P. McMahon
Keyword(s):  
Sonic Hedgehog ◽  
Tooth Development ◽  
Oral Epithelium ◽  
Signaling Proteins ◽  
Conditional Allele ◽  
Oral Ectoderm ◽  
In The Wild ◽  
Crown Formation ◽  
Dental Epithelium

During mammalian tooth development, the oral ectoderm and mesenchyme coordinate their growth and differentiation to give rise to organs with precise shapes, sizes and functions. The initial ingrowth of the dental epithelium and its associated dental mesenchyme gives rise to the tooth bud. Next, the epithelial component folds to give the tooth its shape. Coincident with this process, adjacent epithelial and mesenchymal cells differentiate into enamel-secreting ameloblasts and dentin-secreting odontoblasts, respectively. Growth, morphogenesis and differentiation of the epithelium and mesenchyme are coordinated by secreted signaling proteins. Sonic hedgehog (Shh) encodes a signaling peptide which is present in the oral epithelium prior to invagination and in the tooth epithelium throughout its development. We have addressed the role of Shh in the developing tooth in mouse by using a conditional allele to remove Shh activity shortly after ingrowth of the dental epithelium. Reduction and then loss of Shh function results in a cap stage tooth rudiment in which the morphology is severely disrupted. The overall size of the tooth is reduced and both the lingual epithelial invagination and the dental cord are absent. However, the enamel knot, a putative organizer of crown formation, is present and expresses Fgf4, Wnt10b, Bmp2 and Lef1, as in the wild type. At birth, the size and the shape of the teeth are severely affected and the polarity and organization of the ameloblast and odontoblast layers is disrupted. However, both dentin- and enamel-specific markers are expressed and a large amount of tooth-specific extracellular matrix is produced. This observation was confirmed by grafting studies in which tooth rudiments were cultured for several days under kidney capsules. Under these conditions, both enamel and dentin were deposited even though the enamel and dentin layers remained disorganized. These studies demonstrate that Shh regulates growth and determines the shape of the tooth. However, Shh signaling is not essential for differentiation of ameloblasts or odontoblasts.

scholarly journals BMP Activity Is Required for Tooth Development from the Lamina to Bud Stage

2012 ◽  
Vol 91 (7) ◽  
pp. 690-695 ◽  
Author(s):  
Y. Wang ◽  
L. Li ◽  
Y. Zheng ◽  
G. Yuan ◽  
G. Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Marker ◽  
Tooth Development ◽  
Tooth Germ ◽  
Bmp Signaling ◽  
Expression Of Genes ◽  
Dental Epithelium ◽  
Initiation Stage ◽  
Transgenic Embryos ◽  
Bmp Antagonist

Several Bmp genes are expressed in the developing mouse tooth germ from the initiation to the late-differentiation stages, and play pivotal roles in multiple steps of tooth development. In this study, we investigated the requirement of BMP activity in early tooth development by transgenic overexpression of the extracellular BMP antagonist Noggin. We show that overexpression of Noggin in the dental epithelium at the tooth initiation stage arrests tooth development at the lamina/early-bud stage. This phenotype is coupled with a significantly reduced level of cell proliferation rate and a down-regulation of Cyclin-D1 expression, specifically in the dental epithelium. Despite unaltered expression of genes known to be implicated in early tooth development in the dental mesenchyme and dental epithelium of transgenic embryos, the expression of Pitx2, a molecular marker for the dental epithelium, became down-regulated, suggesting the loss of odontogenic fate in the transgenic dental epithelium. Our results reveal a novel role for BMP signaling in the progression of tooth development from the lamina stage to the bud stage by regulating cell proliferation and by maintaining odontogenic fate of the dental epithelium.

Independent regulation of Dlx2 expression in the epithelium and mesenchyme of the first branchial arch

Development ◽  
2000 ◽  
Vol 127 (2) ◽  
pp. 217-224 ◽  
Author(s):  
B.L. Thomas ◽  
J.K. Liu ◽  
J.L. Rubenstein ◽  
P.T. Sharpe
Keyword(s):  
Tooth Development ◽  
Branchial Arch ◽  
Oral Epithelium ◽  
Upstream Sequence ◽  
Loss Of Function ◽  
Signalling Molecules ◽  
Molar Teeth ◽  
Overlapping Domains ◽  
Upper Molar

Dlx2, a member of the distal-less gene family, is expressed in the first branchial arch, prior to the initiation of tooth development, in distinct, non-overlapping domains in the mesenchyme and the epithelium. In the mesenchyme Dlx2 is expressed proximally, whereas in oral epithelium it is expressed distally. Dlx2 has been shown to be involved in the patterning of the murine dentition, since loss of function of Dlx1 and Dlx2 results in early failure of development of upper molar teeth. We have investigated the regulation of Dlx2 expression to determine how the early epithelial and mesenchymal expression boundaries are maintained, to help to understand the role of these distinct expression domains in patterning of the dentition. Transgenic mice produced with a lacZ reporter construct, containing 3.8 kb upstream sequence of Dlx2, led to the mapping of regulatory regions driving epithelial but not mesenchymal expression in the first branchial arch. We show that the epithelial expression of Dlx2 is regulated by planar signalling by BMP4, which is coexpressed in distal oral epithelium. Mesenchymal expression is regulated by a different mechanism involving FGF8, which is expressed in the overlying epithelium. FGF8 also inhibits expression of Dlx2 in the epithelium by a signalling pathway that requires the mesenchyme. Thus, the signalling molecules BMP4 and FGF8 provide the mechanism for maintaining the strict epithelial and mesenchymal expression domains of Dlx2 in the first arch.

Tissue interactions in embryonic mouse tooth germs

Development ◽  
1970 ◽  
Vol 24 (1) ◽  
pp. 159-171
Author(s):  
Edward J. Kollar ◽  
Grace R. Baird
Keyword(s):  
Enamel Organ ◽  
Oral Epithelium ◽  
Embryonic Mouse ◽  
Tooth Shape ◽  
Structural Specificity ◽  
Dental Papilla ◽  
Tissue Interactions ◽  
Dental Epithelium ◽  
Tooth Germs

The ability of fragments of incisor enamel organ and lip-furrow epithelium from 15- and 16-day old embryonic mice to regulate into harmonious tooth constructions is described. The cervical loop and upper half portions of the incisor enamel organ were confronted with incisor or molar dental papillae. Similar combinations were made from lip-furrow epithelium and incisor or molar papillae. The cultures were grown in the anterior chambers of homologous host eyes. The epithelial fragments from the incisor enamel organ when associated with the dental papillae reconstruct teeth typical in all respects; enamel and dentin matrices are deposited. Lip-furrow epithelium arises from the oral epithelium and is temporally and spatially related to the incisor dental epithelium proper. This ectopic epithelium was confronted by incisor and molar papillae. Harmonious teeth developed in these explants. It is concluded that the ability of the dental papillae to elicit new cytodifferentiative and biochemical syntheses from the lip-furrow epithelium indicates that the dental papillae act inductively during tooth ontogeny. The shape of the teeth reconstructed from enamel organ fragments and lip-furrow epithelium were incisiform or molariform in response to the incisor or molar dental papillae. These data confirm the conclusion that the structural specificity for tooth shape resides in the dental papilla.

scholarly journals Smad7 Regulates Dental Epithelial Proliferation during Tooth Development

2019 ◽  
Vol 98 (12) ◽  
pp. 1376-1385 ◽  
Author(s):  
Z. Liu ◽  
T. Chen ◽  
D. Bai ◽  
W. Tian ◽  
Y. Chen
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cyclin D1 ◽  
Transforming Growth Factor ◽  
Tooth Development ◽  
Tooth Germ ◽  
Transforming Growth Factor Β ◽  
Tooth Size ◽  
Dental Epithelium ◽  
Tooth Morphogenesis

Tooth morphogenesis involves dynamic changes in shape and size as it proceeds through the bud, cap, and bell stages. This process requires exact regulation of cell proliferation and differentiation. Smad7, a general antagonist against transforming growth factor–β (TGF-β) signaling, is necessary for maintaining homeostasis and proper functionality in many organs. While TGF-β signaling is widely involved in tooth morphogenesis, the precise role of Smad7 in tooth development remains unknown. In this study, we showed that Smad7 is expressed in the developing mouse molars with a high level in the dental epithelium but a moderate to weak level in the dental mesenchyme. Smad7 deficiency led to a profound decrease in tooth size primarily due to a severely compromised cell proliferation capability in the dental epithelium. Consistent with the tooth shrinkage phenotype, RNA sequencing (RNA-seq) analysis revealed that Smad7 ablation downregulated genes referred to epithelial cell proliferation and cell cycle G1/S phase transition, whereas the upregulated genes were involved in responding to TGF-β signaling and cell cycle arrest. Among these genes, the expression of Cdkn1a (encoding p21), a negative cell proliferation regulator, was remarkably elevated in parallel with the diminution of Ccnd1 encoding the crucial cell cycle regulator cyclin D1 in the dental epithelium. Meanwhile, the expression level of p-Smad2/3 was ectopically elevated in the developing tooth germ of Smad7 null mice, indicating the hyperactivation of the canonical TGF-β signaling. These effects were reversed by addition of TGF-β signaling inhibitor in cell cultures of Smad7−/− molar tooth germs, with rescued expression of cyclin D1 and cell proliferation rate. In sum, our studies demonstrate that Smad7 functions primarily as a positive regulator of cell proliferation via inhibition of the canonical TGF-β signaling during dental epithelium development and highlight a crucial role for Smad7 in regulating tooth size.

scholarly journals Ameloblastin is a cell adhesion molecule required for maintaining the differentiation state of ameloblasts

2004 ◽  
Vol 167 (5) ◽  
pp. 973-983 ◽  
Author(s):  
Satoshi Fukumoto ◽  
Takayoshi Kiba ◽  
Bradford Hall ◽  
Noriyuki Iehara ◽  
Takashi Nakamura ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Matrix Protein ◽  
Oral Epithelium ◽  
Enamel Matrix Protein ◽  
Mineralized Tissues ◽  
The Matrix ◽  
A Cell ◽  
Dental Epithelium

Tooth morphogenesis results from reciprocal interactions between oral epithelium and ectomesenchyme culminating in the formation of mineralized tissues, enamel, and dentin. During this process, epithelial cells differentiate into enamel-secreting ameloblasts. Ameloblastin, an enamel matrix protein, is expressed by differentiating ameloblasts. Here, we report the creation of ameloblastin-null mice, which developed severe enamel hypoplasia. In mutant tooth, the dental epithelium differentiated into enamel-secreting ameloblasts, but the cells were detached from the matrix and subsequently lost cell polarity, resumed proliferation, and formed multicell layers. Expression of Msx2, p27, and p75 were deregulated in mutant ameloblasts, the phenotypes of which were reversed to undifferentiated epithelium. We found that recombinant ameloblastin adhered specifically to ameloblasts and inhibited cell proliferation. The mutant mice developed an odontogenic tumor of dental epithelium origin. Thus, ameloblastin is a cell adhesion molecule essential for amelogenesis, and it plays a role in maintaining the differentiation state of secretory stage ameloblasts by binding to ameloblasts and inhibiting proliferation.

Sign in / Sign up

Export Citation Format

Share Document