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Diagram showing root morphogenesis in 2 stages: root initiation and root elongation. HERS is formed by fusion of outer enamel epithelium (OEE) and inner enamel epithelium (IEE), which marks the initiation of root formation. The odontoblasts derived from the dental papilla (apical papilla at root elongation stage) form dentin, whereas there are 2 stem cell niches giving rise to cementoblasts (Cb), including the dental follicle (dashed red arrow) and HERS (dashed blue arrow). Some HERS cells eventually become epithelial rests of Malassez (ERM). DFC, dental follicle cell; HERS, Hertwig's epithelial root sheath; SI, stratum intermedium; SR, stellate reticulum.
Source publication
Tooth is made of an enamel-covered crown and a cementum-covered root. Studies on crown dentin formation have been a major focus in tooth development for several decades. Interestingly, the population prevalence for genetic short root anomaly (SRA) with no apparent defects in crown is close to 1.3%. Furthermore, people with SRA itself are predispose...
Citations
... The Wnt signaling pathway is involved in regulation of bone mass and the formation of bone and enamel, dentin, cementum, and periodontal tissues. Although mutations in these signals have been identified and aid in diagnosis they do not always contribute to clinical pathologic or treatment decisions of the entity [9,10]. ...
Purpose of Review
The identification of tumor molecular markers continues to become more widespread. The application of such markers however lags the basic research. This article reviews known signaling pathways and highlights various therapeutics for the treatment of odontogenic tumors.
Recent Findings
Numerous gene mutations have been discovered in the pathogenesis of a multitude of odontogenic tumors. Current research on novel therapeutics for the management of odontogenic tumors focuses mainly on the use of sonic hedgehog pathway inhibitors. These studies however are hindered by low subject enrollment given the low incidence of odontogenic tumors.
Summary
Management of odontogenic tumors is primarily to surgery. Currently, only one therapeutic is becoming widely used albeit in addition to surgery. Given the advances in next generation sequencing, the identification of tumor specific genes will continue to advance. The main challenge going forward is funding new, multi-center trials to research new drugs that target these molecular markers. Until then the morbidity associated with the removal of odontogenic tumors will remain high.
... SHH and BMP signaling also play crucial roles in root development [42,51], with genetic variants in BMP4 having been implicated in tooth agenesis, root maldevelopment, and oral exostoses, similar to the features found in our patients with KCTD1 variants [26]. Therefore, in addition to aberrant WNT and SHH signaling, the root maldevelopment in our patients with KCTD1 variants might have been the effects of disruptive BMP signaling as well. ...
KCTD1 plays crucial roles in regulating both the SHH and WNT/β-catenin signaling pathways, which are essential for tooth development. The objective of this study was to investigate if genetic variants in KCTD1 might also be associated with isolated dental anomalies. We clinically and radiographically investigated 362 patients affected with isolated dental anomalies. Whole exome sequencing identified two unrelated families with rare (p.Arg241Gln) or novel (p.Pro243Ser) variants in KCTD1. The variants segregated with the dental anomalies in all nine patients from the two families. Clinical findings of the patients included taurodontism, unseparated roots, long roots, tooth agenesis, a supernumerary tooth, torus palatinus, and torus mandibularis. The role of Kctd1 in root development is supported by our immunohistochemical study showing high expression of Kctd1 in Hertwig epithelial root sheath. The KCTD1 variants in our patients are the first variants found to be located in the C-terminal domain, which might disrupt protein–protein interactions and/or SUMOylation and subsequently result in aberrant WNT-SHH-BMP signaling and isolated dental anomalies. Functional studies on the p.Arg241Gln variant are consistent with an impact on β-catenin levels and canonical WNT signaling. This is the first report of the association of KCTD1 variants and isolated dental anomalies.
... The evolutionary and functional significance of mammalian tooth-crown shape and wear patterns is more extensively studied and better understood (Crompton, 1971;Lucas, 2004) than other aspects of tooth structure, such as tooth-root morphology. Roots are an integral part of the tooth, and are physically connected to the tooth-crown and transmit forces during mastication to the dentary and skull (Wang & Feng, 2017). Like the tooth-crowns, roots can also be expected to vary in their functional role and position within the tooth-row (Spencer, 2003). ...
... The development and periodic repair of organs (hair, teeth, skin, tongue papillae, etc.) are crucial for the regeneration and maintenance of normal function after organ wear and tear [1,2]. The activation of initiation signals for organ development and repair is crucial for inducing regeneration of cells or tissues from the remaining stage to the initial stage [3]. The activation of organ development or periodic repair initiation signals is programmed in a process that is not the same as the mechanism of immune repair in the body after organ damage. ...
Objective
Fungiform papillae contain taste buds and play a critical role in mastication and the gustatory system. In this study, we report a series of sequential observations of organogenesis of fungiform papillae in miniature pigs, as well as changes in the expression of BMP2, BMP4, Wnt5a, Sox2, and Notch1 signaling pathway components.
Design
In this study, we investigated the spatiotemporal expression patterns of BMP, Wnt, Sox2 and Notch in the fungiform papillae of miniature pigs at the bud stage (E40), cap stage (E50) and bell stage (E60). Pregnant miniature pigs were obtained, and the samples were processed for histological staining. Immunohistochemistry and real-time PCR were used to detect the mRNA and protein expression levels of BMP2, BMP4, Wnt5a, Sox2, and Notch1.
Results
At E40, fungiform papillae were present on the anterior two-thirds of the tongue in a specific array and pattern. The fungiform papillae were enlarged and basically developed at E50 and were largest at the earlier stage (E60). Most of the BMP2 was concentrated in the epithelial layer and the connective tissue core of the fungal papilloma and gradually accumulated from E40-E60. BMP-4 was weakly expressed in the fungiform papillae epithelia, but BMP-4-positive cells were also observed in the developing tongue muscle at E50 and E60. Wnt5a-positive cells were observed in the fungiform papillae epithelia and developing tongue muscle at all three time points. Sox2-positive cells were observed only in fungiform papillae epithelial cells, and Notch1-positive cells could not be detected.
Conclusions
This study provides primary data regarding the morphogenesis and expression of developmental signals in the fungiform papillae of miniature pigs, establishing a foundation for further research in both this model and humans.
... Previous studies have shown that various growth factors are involved in tooth development, including major signals such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), sonic hedgehog (SHH) and wingless-type MMTV integration site family (WNT) (Bei, 2009;Balic & Thesleff, 2015;Li et al., 2017;Nakatomi et al., 2006;Tucker & Sharpe, 2004;Wang & Feng, 2017). Of these, involvement of BMP, SHH and WNT signals has been well examined in tooth root development. ...
Fibroblast growth factor (FGF) signalling plays a crucial role in the morphogenesis of multiple tissues including teeth. While the role of the signal has been studied in tooth crown development, little is known about root development. Of several FGF ligands involved in hard tissue formation, we suggest that FGF18 regulates the development of murine tooth roots. We implanted FGF18‐soaked heparin beads into the lower first molar tooth buds at postnatal day 6 (P6), followed by transplantation under the kidney capsule. After 3 weeks, FGF18 significantly facilitated root elongation and periodontal tissue formation compared to the control. In situ hybridisation showed that Fgf18 transcripts were initially localised in the dental pulp along Hertwig's epithelial root sheath at P6 and P10 and subsequently in the dental follicle cells at P14. Fgf receptors were expressed in various dental tissues during these stages. In vitro analysis using the dental pulp stem cells revealed that FGF18 inhibited cell proliferation and decreased expression levels of osteogenic markers, Runx2 , Alpl and Sp7 . Consistently, after 1 week of kidney capsule transplantation, FGF18 application did not induce the expression of Sp7 and Bsp , but upregulated Periostin in the apical region of dental mesenchyme in the grafted molar. These findings suggest that FGF18 facilitates molar root development by regulating the calcification of periodontal tissues.
... The Hertwig's epithelial root sheath (HERS) plays a critical role in root formation (13,14), determining the shape, size and number of dental roots (15). Genetic studies have identified that several molecules, such as Nfic, Osterix, β-catenin, and sonic hedgehog, constitute key factors in root formation (13). ...
... The Hertwig's epithelial root sheath (HERS) plays a critical role in root formation (13,14), determining the shape, size and number of dental roots (15). Genetic studies have identified that several molecules, such as Nfic, Osterix, β-catenin, and sonic hedgehog, constitute key factors in root formation (13). Since these molecules regulate root formation, they could help to understand the mechanisms determining the number of canals. ...
... HERS is known to play a critical role in root formation (13,14) and determining the shape, size, and number of dental roots (15). The number of roots is determined by the number of inward-bending horizontal processes, called interradicular or diaphragmatic processes (DP), that are emitted from the epithelial diaphragm shortly after crown formation; if two DP are extended, two roots will be formed, with three DP, three roots will be formed, and so on; if no DP is formed, then a single-rooted tooth will be the result. ...
Background: Although millions of root canal treatments are performed globally on a daily basis, factors that determine the number of main root canals in a tooth have not yet been elucidated. Variations in the number of root canals in different teeth is of utmost importance in clinical practice. However, clinicians aren´t aware about the determinants of such number, let alone these determinants have been approached in the literature, to the best of our knowledge. Purpose: This narrative review aimed to integrate the potential mechanisms involved in determining the number of main canals in a permanent tooth. Methods: We used the search terms "root canal number," "root canal morphology," "tooth morphology," "root development," and "root formation" to identify articles from the PubMed and Scopus databases. Results: 57 articles and 2 books were obtained. A multifactorial basis is plausible considering the influence of anthropological, demographic, environmental, genetic, epigenetic, tooth size related mechanisms and the pivotal role of Hertwig's epithelial root sheath. Live-cell imaging techniques, mathematical models, quantitative genetics and dental phenomics could provide insightful information in the near future. Conclusions: Overall, it seems that the potential mechanisms determining the number of main canals in a tooth have a multifactorial basis. The orchestrating role of the Hertwig's epithelial root sheath seems pivotal, although the specific regulatory signals that induce or repress its diaphragmatic processes remain unknown. However, there is a dire need for molecular studies that help unveil these and other potential mechanisms involved.
... Then HERS continues to migrate downward to shape the root, and adjacent dental papilla cells (DPCs) and dental follicle cells (DFCs) differentiate into matrix-producing odontoblasts and cementoblasts. Multiple signaling pathways like wingless (Wnt), hedgehog (Hh) and bone morphogenetic protein (Bmp) interact to orchestrate normal tooth root morphogenesis [3]. However, the developing root is susceptible to endogenous and exogenous factors, leading to root dysplasia characterized in short root, absent furcation or curved roots [3][4][5]. ...
... Multiple signaling pathways like wingless (Wnt), hedgehog (Hh) and bone morphogenetic protein (Bmp) interact to orchestrate normal tooth root morphogenesis [3]. However, the developing root is susceptible to endogenous and exogenous factors, leading to root dysplasia characterized in short root, absent furcation or curved roots [3][4][5]. To date, we have poor knowledge about the potential mechanism. ...
Background
CDC42 is a member of Rho GTPase family, acting as a molecular switch to regulate cytoskeleton organization and junction maturation of epithelium in organ development. Tooth root pattern is a highly complicated and dynamic process that dependens on interaction of epithelium and mesenchyme. However, there is a lack of understanding of the role of CDC42 during tooth root elongation.
Methods
The dynamic expression of CDC42 was traced during tooth development through immunofluorescence staining. Then we constructed a model of lentivirus or inhibitor mediated Cdc42 knockdown in Herwig’s epithelial root sheath (HERS) cells and dental papilla cells (DPCs), respectively. Long-term influence of CDC42 abnormality was assessed via renal capsule transplantation and in situ injection of alveolar socket.
Results
CDC42 displayed a dynamic spatiotemporal pattern, with abundant expression in HERS cells and apical DPCs in developing root. Lentivirus-mediated Cdc42 knockdown in HERS cells didn’t disrupt cell junctions as well as epithelium-mesenchyme transition. However, inhibition of CDC42 in DPCs undermined cell proliferation, migration and odontogenic differentiation. Wnt/β-catenin signaling as the downstream target of CDC42 modulated DPCs’ odontogenic differentiation. The transplantation and in situ injection experiments verified that loss of CDC42 impeded root extension via inhibiting the proliferation and differentiation of DPCs.
Conclusions
We innovatively revealed that CDC42 was responsible for guiding root elongation in a mesenchyme-specific manner. Furthermore, CDC42-mediated canonical Wnt signaling regulated odontogenic differentiation of DPCs during root formation.
... The Wnt signaling pathway is deeply involved in these processes throughout life, and includes characteristic functions of maintenance of the stem cell niche, in addition to trophic effects such as cell proliferation, differentiation, and apoptosis regulation 3,4) . Wnt signals also vary at different sites depending on signaling strength and degree of tissue differentiation, even if the signals act on the same cells, indicating that Wnt signals have various biological functions and spatiotemporal specificity 5,6) . For example, the β-catenin pathway is inactive in the absence of Wnt ligands, and becomes activated when the ligand concentration exceeds that of antagonists 7) . ...
In organs, multiple functionally differentiated cells and stem cells are organized to express specific functions through a series of complex interactions. The Wnt signaling pathway is deeply involved in these processes throughout life. The dependence of Wnt signaling on spatiotemporal specificity and the changes in vivo interactions caused by the balance and distribution of Wnt ligands and antagonists. Regeneration is thought to involve reconstitution of the growth mechanism, and thus control of stem cells and tissue regeneration has been attempted by mimicking canonical Wnt signals. Wnt10a has been reported to be involved in tooth development and regeneration. These findings indicate the importance of understanding and reproducing involvement of Wnt10a in dental pulp regeneration for development of regenerative dental treatment. Accordingly, we examined the spatiotemporal specificity of Wnt signals involved in dental pulp regeneration by morphologically examining changes in Wnt signals over time in regenerated dental pulp using ectopic tooth root implantation. Expression levels of Wnt10a and DKK1 in regenerated dental pulp suggest that Wnt expression does not increase continuously with time as regeneration increases, which reflects the spatiotemporal specificity of Wnt. In addition, the Dkk1 expression kinetics had a phase shift relative to those of Wnt10a: Dkk1 expression was low when that of Wnt10a was high, and Wnt10a expression decreased when Dkk1 expression increased. These results suggest that canonical Wnt signals have an elaborate control mechanism in regenerated pulp, as suggested in previous reports. Moreover, Wnt reflects the percentage of regenerated pulp. Therefore Wnt is a potential biomarker of pulp regeneration.
... Dental pulp has many types of tissue, including blood vessels and nerve fibers, in addition to odontoblasts, and this indicates the need to examine the relationships of these tissues with Wnt10a in more detail. Contrasting biological functions might be shown by the same cell depending on the strength of Wnt signaling, cell species, and level of cell differentiation 39,40) . DKK1 increases with increased expression of Wnt6, a canonical Wnt signal, upon odontoblast differentiation, as seen with Wnt10a. ...
The aim of regenerative medicine is to restore the original functions of tissues and organs damaged by disease or impairment. Stem cell transfusion has been used clinically as regenerative therapy in a wide range of fields. This therapy promotes regeneration of partially damaged tissues or organs by transfer of tissue stem cells. Teeth are produced from dental germ, which is induced by interactions between epithelial and mesenchymal stem cells. Wnt signals are heavily involved in this process. Furthermore, it has been shown that β-catenin is expressed in the nucleus of odontoblasts and dentinal cells located immediately under repaired dentine after pulpotomy, and that macrophages in dental pulp express Wnt10a, suggesting involvement of Wnt10a in odontoblasts in generation and repair processes. However, little is known about the involvement of Wnt10a in odontoblasts in regenerated pulp tissues. Hayashi et al. transplanted dental pulp, bone marrow, adipose stem cells, or culture supernatants derived from each of them in the ectopic tooth transplantation. As a result, we have succeeded in regenerating dental pulp tissue that expresses the dental pulp marker TRH-DE, regardless of the transplantation. In this study, we used this model to examine morphologically how Wnt10a and odontoblasts change with time in regenerated dental pulp. We then analyzed the dynamics of Wnt10a in dentinal induction in dental pulp stem cells. The results of this study showed an increase in odontoblasts with increased regeneration of dental pulp, and these odontoblasts expressed Wnt10a. Expression of DSPP increases upon inhibition of expression of DKK1, and induction of dentinal differentiation occurs via expression of Wnt10a in dental pulp regeneration. Therefore, Wnt10a is a candidate as a non-cellular agent for induction of dental pulp regeneration with dentine-inducing capacity.
... The sources of the motive force include the dental follicle surrounding the tooth bud, osteogenic activities in the alveolar bone surrounding the tooth root, the formation of the periodontal ligament (PDL) and traction forces generated by the fibers therein, and the development of the tooth root and the cementum in the apical region. Traditionally, tooth eruption has been regarded as a separate and distinct process from tooth root formation, as teeth can emerge into the oral cavity without roots or PDLs [45,46]. However, recent studies support the emerging theory that these two processes are intertwined [36,39]. ...
Primary failure of eruption (PFE) is a rare disorder defined as incomplete tooth eruption despite the presence of a clear eruption pathway. PFE is known to be caused by rare variants in the parathyroid hormone 1 receptor gene (PTH1R). Although several PTH1R variants have been reported, the etiology of PFE remains unclear. However, important studies that help elucidate the pathology of PFE have recently been published. The purpose of this review is to summarize current treatment options, clinical symptoms or phenotypes for diagnosis, genetic information including solid evidence in mouse disease models and disease-specific induced pluripotent stem cells, thus approaching the etiology of PFE from the perspective of the latest research.
