Talk:Integumentary System - Tooth Development

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Cite this page: Hill, M.A. (2021, June 18) Embryology Integumentary System - Tooth Development. Retrieved from


Zhang S, Li X, Wang S, Yang Y, Guo W, Chen G & Tian W. (2020). Immortalized Hertwig's epithelial root sheath cell line works as model for epithelial-mesenchymal interaction during tooth root formation. J. Cell. Physiol. , 235, 2698-2709. PMID: 31512758 DOI. Immortalized Hertwig's epithelial root sheath cell line works as model for epithelial-mesenchymal interaction during tooth root formation.

Abstract Hertwig's epithelial root sheath (HERS) is critical for epithelial-mesenchymal interaction (EMI) during tooth root formation. However, the exact roles of HERS in odontogenic differentiation by EMI have not been well characterized, because primary HERS cells are difficult to obtain. Immortalized cell lines constitute crucial scientific tools, while there are few HERS cell lines available. Our previous study has successfully established immortalized HERS cell lines. Here, we confirmed the phenotype of our HERS-H1 by verifying its characteristics and functions in odontogenic differentiation through EMI. The HERS-H1-conditioned medium (CM-H1) effectively enhanced odontogenic differentiation of dental papilla cells (DPCs) in vitro. Furthermore, Smad4 and p-Smad1/5/8 were significantly activated in DPCs treated with CM-H1, and this activation was attenuated by noggin. In vivo, our implanted recombinants of HERS-H1 and DPCs exhibited mineralized tissue formation and expression of Smad4, p-Smad1/5/8, and odontogenic differentiation markers. Our results indicated that HERS-H1 promoted DPCs odontoblastic differentiation via bone morphogenetic protein/Smad signaling. HERS-H1 exhibits relevant key molecular characteristics and constitutes a new biological model for basic research on HERS and the dental EMI during root development and regeneration. © 2019 Wiley Periodicals, Inc. KEYWORDS: BMP/Smad signaling; Hertwig's epithelial root sheath cell; dental epithelial-mesenchymal interaction; odontogenic differentiation PMID: 31512758 DOI: 10.1002/jcp.29174


Parathyroid hormone-related peptide (1-34) promotes tooth eruption and inhibits osteogenesis of dental follicle cells during tooth development

J Cell Physiol. 2019 Jul;234(7):11900-11911. doi: 10.1002/jcp.27857. Epub 2018 Dec 24.

Zhang J1,2,3, Liao L1,2,4, Li Y1,3, Xu Y1,3, Guo W1,2,4, Tian W1,2,5, Zou S1,3.

Dental follicle cells (DFCs) activate and recruit osteoclasts for tooth development and tooth eruption, whereas DFCs themselves differentiate into osteoblasts to form alveolar bone surrounding tooth roots through the interaction with Hertwig's epithelial root sheath (HERS). Also during tooth development, parathyroid hormone-related peptide (PTHrP) is expressed surrounding the tooth germ. Thus, we aimed to investigate the effect of PTHrP (1-34) on bone resorption and osteogenesis of DFCs in vitro and in vivo. In vitro studies demonstrated that DFCs cocultured with HERS cells expressed higher levels of BSP and OPN than the DFCs control group, whereas cocultured DFCs treated with PTHrP (1-34) had lower expressions of ALP, RUNX2, BSP, and OPN than the cocultured DFCs control group. Moreover, we found PTHrP (1-34) inhibited osteogenesis of cocultured DFCs by inactivating the Wnt/β-catenin pathway. PTHrP (1-34) also increased the expression of RANKL/OPG ratio in DFCs. Consistently, in vivo study found that PTHrP (1-34) accelerated tooth eruption and inhibited alveolar bone formation. Therefore, these results suggest that PTHrP (1-34) accelerates tooth eruption and inhibits osteogenesis of DFCs by inactivating Wnt/β-catenin pathway. © 2018 Wiley Periodicals, Inc. KEYWORDS: Hertwig's epithelial root sheath cell; dental follicle cell; osteogenesis; parathyroid hormone-related peptide; tooth eruption PMID: 30584670 DOI: 10.1002/jcp.27857

Development of immortalized Hertwig's epithelial root sheath cell lines for cementum and dentin regeneration

Stem Cell Res Ther. 2019 Jan 3;10(1):3. doi: 10.1186/s13287-018-1106-8.

Li X1,2,3,4, Zhang S1,2,3, Zhang Z1,2,3,5, Guo W1,2,3,6, Chen G7,8,9, Tian W10,11,12,13.


BACKGROUND: Hertwig's epithelial root sheath (HERS) is important in guiding tooth root formation by differentiating into cementoblasts through epithelial-mesenchymal transition (EMT) and inducing odontoblastic differentiation of dental papilla through epithelial-mesenchymal interaction (EMI) during the tooth root development. Thus, HERS cells are critical for cementum and dentin formation and might be a potential cell source to achieve tooth root regeneration. However, limited availability and lifespan of primary HERS cells may represent an obstacle for biological investigation and therapeutic use of tooth tissue engineering. Therefore, we constructed, characterized, and tested the functionality of immortalized cell lines in order to produce a more readily available alternative to HERS cells.

METHODS: Primary HERS cells were immortalized via infection with lentivirus vector containing the gene encoding simian virus 40 Large T Antigen (SV40LT). Immortalized HERS cell subclones were isolated using a limiting dilution method, and subclones named HERS-H1 and HERS-C2 cells were isolated. The characteristics of HERS-H1 and HERS-C2 cells, including cell proliferation, ability of epithelial-mesenchymal transformation and epithelial-mesenchymal interaction, were determined by CCK-8 assay, immunofluorescence staining, and real-time PCR. The cell differentiation into cementoblast-like cells or periodontal fibroblast-like cells was confirmed in vivo. And the inductive influence of the cell lines on dental papilla cells (DPCs) was also confirmed in vivo.

RESULTS: HERS-H1 and HERS-C2 cells share some common features with primary HERS cells such as epithelial-like morphology, positive expression of CK14, E-Cadherin, and Vimentin, and undergoing EMT in response to TGF-beta. HERS-C2 cells showed the EMT characteristics and could differentiate into cementum-forming cells in vitro and generate cementum-like tissue in vivo. HERS-H1 could induce the differentiation of DPCs into odontoblasts in vitro and generation of dentin-like tissue in vivo.

CONCLUSIONS: We successfully isolated and characterized novel cell lines representing two key features of HERS cells during the tooth root development and which were useful substitutes for primary HERS cells, thereby providing a biologically relevant, unlimited cell source for studies on cell biology, developmental biology, and tooth root regeneration.

KEYWORDS: Cementum; Dentin; Hertwig’s epithelial root sheath; Tooth regeneration PMID: 30606270 PMCID: PMC6319004 DOI: 10.1186/s13287-018-1106-8

Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption

Akira Takahashi, Mizuki Nagata, Aditi Gupta, Yuki Matsushita, Tetsutaro Yamaguchi, Koji Mizuhashi, Koutaro Maki, Antonio C. Ruellas, Lucia S. Cevidanes, Henry M. Kronenberg, Noriaki Ono, Wanida Ono

Proceedings of the National Academy of Sciences Jan 2019, 116 (2) 575-580; DOI: 10.1073/pnas.1810200115


Formation of functional skeletal tissues requires highly organized steps of mesenchymal progenitor cell differentiation. The dental follicle (DF) surrounding the developing tooth harbors mesenchymal progenitor cells for various differentiated cells constituting the tooth root–bone interface and coordinates tooth eruption in a manner dependent on signaling by parathyroid hormone-related peptide (PTHrP) and the PTH/PTHrP receptor (PPR). However, the identity of mesenchymal progenitor cells in the DF and how they are regulated by PTHrP-PPR signaling remain unknown. Here, we show that the PTHrP-PPR autocrine signal maintains physiological cell fates of DF mesenchymal progenitor cells to establish the functional periodontal attachment apparatus and orchestrates tooth eruption. A single-cell RNA-seq analysis revealed cellular heterogeneity of PTHrP+ cells, wherein PTHrP+ DF subpopulations abundantly express PPR. Cell lineage analysis using tamoxifen-inducible PTHrP-creER mice revealed that PTHrP+ DF cells differentiate into cementoblasts on the acellular cementum, periodontal ligament cells, and alveolar cryptal bone osteoblasts during tooth root formation. PPR deficiency induced a cell fate shift of PTHrP+ DF mesenchymal progenitor cells to nonphysiological cementoblast-like cells precociously forming the cellular cementum on the root surface associated with up-regulation of Mef2c and matrix proteins, resulting in loss of the proper periodontal attachment apparatus and primary failure of tooth eruption, closely resembling human genetic conditions caused by PPR mutations. These findings reveal a unique mechanism whereby proper cell fates of mesenchymal progenitor cells are tightly maintained by an autocrine system mediated by PTHrP-PPR signaling to achieve functional formation of skeletal tissues.


Persistent Wnt/β-catenin signaling in mouse epithelium induces the ectopic Dspp expression in cheek mesenchyme

Organogenesis. 2018 Dec 20:1-12. doi: 10.1080/15476278.2018.1557026. [Epub ahead of print]

Zhou N1, Li N1, Liu J1, Wang Y1, Gao J1, Wu Y1, Chen X1, Liu C1, Xiao J1. Author information Abstract Tooth development is accomplished by a series of epithelial-mesenchyme interactions. Epithelial Wnt/β-catenin signaling is sufficient to initiate tooth development by activating Shh, Bmps, Fgfs and Wnts in dental epithelium, which in turn, triggered the expression of odontogenic genes in the underlying mesenchyme. Although constitutive activation of Wnt/β-catenin signaling in oral ectoderm resulted in the continuous tooth formation throughout the life span, if the epithelial Wnt/β-catenin signaling could induce the mesenchyme other than oral mesenchyme still required to be elucidated. In this study, we found that in the K14-cre; Ctnnb1ex3f mice, the markers of dental epithelium, such as Pitx2, Shh, Bmp2, Fgf4, and Fgf8, were not only activated in the oral ectoderm, but also in the cheek epithelium. Surprisingly, the underlying cheek mesenchymal cells were elongated and expressed Dspp. Further investigations detected that the expression of Msx1 and Runx2 extended from oral to cheek mesenchyme. These findings suggested that epithelial Wnt/β-catenin signaling was capable of inducing Dspp expression in non-dental mesenchyme. Moreover, Dspp expression in the K14-cre; Ctnnb1ex3f oral mesenchyme was activated earlier than that in the wild type littermates. In contrast, although the elongated oral epithelial cells were detected in the K14-cre; Ctnnb1ex3f mice, the Amelogenin expression was suppressed. The differential effects of the persistent epithelial Wnt/β-catenin signaling on ameloblast and odontoblast differentiation might result from the altered BMP signaling. In summary, our findings suggested that the epithelial Wnt/β-catenin signaling could induce craniofacial mesenchyme into odontogenic program and promote odontoblast differentiation.

KEYWORDS: BMP signaling; Wnt/β-catenin signaling; odontogenic differentiation; tissue interaction; tooth development PMID: 30570432 DOI: 10.1080/15476278.2018.1557026

Phosphophoryn and Dentin Sialoprotein Effects on Dental Pulp Cell Migration, Proliferation, and Differentiation

Dent J (Basel). 2018 Dec 10;6(4). pii: E70. doi: 10.3390/dj6040070.

Chuang SF1,2, Chen YH3,4, Ma P5, Ritchie HH6.


Phosphophoryn (PP) and dentin sialoprotein (DSP) are two of the most abundant dentin matrix non-collagenous proteins, and are derived from dentin sialoprotein-phosphophoryn (DSP-PP) mRNA. Mutations in the DSP-PP gene are linked to dentinogenesis imperfecta II and III. Previously, we reported transient DSP-PP expression in preameloblast cells first, followed by co-expression in preameloblasts and young odontoblasts, and finally sustained expression in odontoblasts. This phenomenon raised the possibility that DSP/PP proteins secreted by preameloblasts might promote dental pulp cell migration toward the dental pulp border and promote dental pulp cell differentiation. To examine the effects of DSP/PP proteins on dental pulp cell development, we investigated:(1) native PP effects on dental pulpcell migration and matrix protein expression; and (2) recombinant DSP/PP protein effects on cell proliferation and differentiation. We found that PP promoted cell migration and the expression of high levels of Col type I and PP in dental pulp cells. The addition of recombinant DSP/PP proteins affected cell proliferation and differentiation in a dental pulp cell line. These findings strongly suggest that DSP/PP may modulate cell migration, cell proliferation and differentiation, thus leading to dentin formation. DSP/PP protein may be useful clinically for pulp tissue regeneration.

KEYWORDS: cell migration; dental pulp cells; dentin sialoprotein (DSP); dentinogenesis; differentiation; phosphophoryn (PP) PMID: 30544680 PMCID: PMC6313708 DOI: 10.3390/dj6040070

Upstream Enhancer Elements of Shh Regulate Oral and Dental Patterning

J Dent Res. 2018 Feb 1:22034518758642. doi: 10.1177/0022034518758642. [Epub ahead of print]

Seo H1,2,3, Amano T4, Seki R4, Sagai T4, Kim J1,2, Cho SW1, Shiroishi T4.


Sonic hedgehog ( Shh) is important in pattern formation during development. Shh transcription is modulated by a long-range regulatory mechanism containing a number of enhancers, which are spread over nearly 850 kb in the mouse genome. Shh enhancers in the nervous system have been found between intron and 430 kb upstream of Shh. Enhancers in the oral cavity, pharynx, lung, gut, and limbs have been discovered between 610 kb and 850 kb upstream of Shh. However, the intergenic region ranging from 430 to 610 kb upstream of Shh remains to be elucidated. In the present study, we found a novel long-range enhancer located 558 kb upstream of Shh. The enhancer showed in vivo activity in oral cavity and whiskers. A targeted deletion from the novel enhancer to mammal reptile conserved sequence 1 (MRCS1), which is a known enhancer of Shh in oral cavity, resulted in supernumerary molar formation, confirming the essential role of this intergenic region for Shh transcription in teeth. Furthermore, we clarified the binding of Lef1/Tcfs to the new enhancer and MRCS1, suggesting that Wnt/β-catenin signaling regulates Shh signaling in the oral cavity via these enhancers. KEYWORDS: Shh protein; Wnt signaling pathway; conserved sequence; embryonic development; sequence deletion; tooth germ PMID: 29481312 DOI: 10.1177/0022034518758642

Hey1 and Hey2 are differently expressed during mouse tooth development

Gene Expr Patterns. 2018 Jan;27:99-105. doi: 10.1016/j.gep.2017.11.004. Epub 2017 Nov 16.

Kibe K1, Nakatomi M2, Kataoka S3, Toyono T3, Seta Y3. Author information Abstract The Hey family (also known as Chf, Herp, Hesr, and Hrt) is a set of Hairy/Enhancer of Split-related basic helix-loop-helix type transcription factors. Hey1, Hey2, and HeyL have been identified in mammals. Although Hey proteins are known to regulate cardiovascular development, muscle homeostasis, osteogenesis, neurogenesis, and oncogenesis, their roles in tooth development have been largely obscure. Therefore, this study aimed to clarify detailed spatiotemporal expression patterns of Hey1 and Hey2 in developing molars and incisors of mice by section in situ hybridization. Hey1 and Hey2 were not significantly expressed in tooth germs at epithelial thickening, bud, and cap stages during molar development. In the dental epithelium in molars at the bell stage and incisors, Hey2 transcripts were restricted to the undifferentiated inner enamel epithelium and down-regulated in preameloblasts and ameloblasts. On the other hand, Hey1 was mainly expressed in preameloblasts and down-regulated in differentiated ameloblasts. Both genes were not significantly expressed in other dental epithelial tissues, including the outer enamel epithelium, stellate reticulum, and stratum intermedium cells. In the dental mesenchyme, Hey1 was intensely transcribed in the subodontoblastic layer of the dental pulp in both molars and incisors, whereas Hey2 was barely detectable in mesenchymal components. Our data implied that Hey2 function is restricted to transient amplifying cells of the ameloblast cell lineage and that Hey1 plays a role in the composition of the subodontoblastic layer, in addition to ameloblast differentiation. These findings provide novel clues for the better understanding of tooth development.

Copyright © 2017 Elsevier B.V. All rights reserved.

KEYWORDS: Ameloblasts; Basic helix-loop-helix transcription factors; Dental pulp; Enamel organ; Preameloblasts; Subodontoblastic layer PMID: 29155305


PAX9 gene mutations and tooth agenesis: A review

Clin Genet. 2017 Feb 2. doi: 10.1111/cge.12986. [Epub ahead of print]

Bonczek O1,2, Balcar VJ3, Šerý O1,2.


Paired box 9 (PAX9) is one of the best-known transcription factors involved in the development of human dentition. Mutations in PAX9 gene could, therefore, seriously influence the number, position and morphology of the teeth in an affected individual. To date, over 50 mutations in the gene have been reported as associated with various types of dental agenesis (congenitally missing teeth) and other inherited dental defects or variations. The most common consequence of PAX9 gene mutation is the autosomal-dominant isolated (non-syndromic) oligodontia or hypodontia. In the present review, we are summarizing all known PAX9 mutations as well as their nature and precise loci in the DNA sequence of the gene. Where necessary, we have revised the loci of the mutations in line with the reference sequence of the PAX9 gene as it appears in the current DNA databases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. KEYWORDS: PAX9; gene; hypodontia; mutation; oligodontia

PMID 28155232


Epithelial stratification and placode invagination are separable functions in early morphogenesis of the molar tooth

Development. 2016 Feb 15;143(4):670-81. doi: 10.1242/dev.130187. Epub 2016 Jan 11.

Li J1, Chatzeli L1, Panousopoulou E1, Tucker AS1, Green JB2.


Ectodermal organs, which include teeth, hair follicles, mammary ducts, and glands such as sweat, mucous and sebaceous glands, are initiated in development as placodes, which are epithelial thickenings that invaginate and bud into the underlying mesenchyme. These placodes are stratified into a basal and several suprabasal layers of cells. The mechanisms driving stratification and invagination are poorly understood. Using the mouse molar tooth as a model for ectodermal organ morphogenesis, we show here that vertical, stratifying cell divisions are enriched in the forming placode and that stratification is cell division dependent. Using inhibitor and gain-of-function experiments, we show that FGF signalling is necessary and sufficient for stratification but not invagination as such. We show that, instead, Shh signalling is necessary for, and promotes, invagination once suprabasal tissue is generated. Shh-dependent suprabasal cell shape suggests convergent migration and intercalation, potentially accounting for post-stratification placode invagination to bud stage. We present a model in which FGF generates suprabasal tissue by asymmetric cell division, while Shh triggers cell rearrangement in this tissue to drive invagination all the way to bud formation. © 2016. Published by The Company of Biologists Ltd. KEYWORDS: Asymmetric cell division; Ectodermal organ; Invagination; Morphogenesis; Placode

PMID 26755699


Coevolutionary patterning of teeth and taste buds

Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):E5954-62. doi: 10.1073/pnas.1514298112. Epub 2015 Oct 19.

Bloomquist RF1, Parnell NF2, Phillips KA2, Fowler TE2, Yu TY3, Sharpe PT3, Streelman JT4.


Teeth and taste buds are iteratively patterned structures that line the oro-pharynx of vertebrates. Biologists do not fully understand how teeth and taste buds develop from undifferentiated epithelium or how variation in organ density is regulated. These organs are typically studied independently because of their separate anatomical location in mammals: teeth on the jaw margin and taste buds on the tongue. However, in many aquatic animals like bony fishes, teeth and taste buds are colocalized one next to the other. Using genetic mapping in cichlid fishes, we identified shared loci controlling a positive correlation between tooth and taste bud densities. Genome intervals contained candidate genes expressed in tooth and taste bud fields. sfrp5 and bmper, notable for roles in Wingless (Wnt) and bone morphogenetic protein (BMP) signaling, were differentially expressed across cichlid species with divergent tooth and taste bud density, and were expressed in the development of both organs in mice. Synexpression analysis and chemical manipulation of Wnt, BMP, and Hedgehog (Hh) pathways suggest that a common cichlid oral lamina is competent to form teeth or taste buds. Wnt signaling couples tooth and taste bud density and BMP and Hh mediate distinct organ identity. Synthesizing data from fish and mouse, we suggest that the Wnt-BMP-Hh regulatory hierarchy that configures teeth and taste buds on mammalian jaws and tongues may be an evolutionary remnant inherited from ancestors wherein these organs were copatterned from common epithelium. KEYWORDS: bipotency; placode patterning; plasticity; quantitative trait loci; tooth/taste bud development

PMID 26483492

Tooth and scale morphogenesis in shark: an alternative process to the mammalian enamel knot system

BMC Evol Biol. 2015 Dec 24;15:292. doi: 10.1186/s12862-015-0557-0.

Debiais-Thibaud M1, Chiori R2,3, Enault S4, Oulion S5, Germon I6, Martinand-Mari C7, Casane D8,9, Borday-Birraux V10,11.


BACKGROUND: The gene regulatory network involved in tooth morphogenesis has been extremely well described in mammals and its modeling has allowed predictions of variations in regulatory pathway that may have led to evolution of tooth shapes. However, very little is known outside of mammals to understand how this regulatory framework may also account for tooth shape evolution at the level of gnathostomes. In this work, we describe expression patterns and proliferation/apoptosis assays to uncover homologous regulatory pathways in the catshark Scyliorhinus canicula. RESULTS: Because of their similar structural and developmental features, gene expression patterns were described over the four developmental stages of both tooth and scale buds in the catshark. These gene expression patterns differ from mouse tooth development, and discrepancies are also observed between tooth and scale development within the catshark. However, a similar nested expression of Shh and Fgf suggests similar signaling involved in morphogenesis of all structures, although apoptosis assays do not support a strictly equivalent enamel knot system in sharks. Similarities in the topology of gene expression pattern, including Bmp signaling pathway, suggest that mouse molar development is more similar to scale bud development in the catshark. CONCLUSIONS: These results support the fact that no enamel knot, as described in mammalian teeth, can be described in the morphogenesis of shark teeth or scales. However, homologous signaling pathways are involved in growth and morphogenesis with variations in their respective expression patterns. We speculate that variations in this topology of expression are also a substrate for tooth shape evolution, notably in regulating the growth axis and symmetry of the developing structure.

PMID 26704180


Three-dimensional analysis of the early development of the dentition

Aust Dent J. 2014 Jun;59 Suppl 1:55-80. doi: 10.1111/adj.12130. Epub 2014 Feb 4.

Peterkova R1, Hovorakova M, Peterka M, Lesot H.


Tooth development has attracted the attention of researchers since the 19th century. It became obvious even then that morphogenesis could not fully be appreciated from two-dimensional histological sections. Therefore, methods of three-dimensional (3D) reconstructions were employed to visualize the surface morphology of developing structures and to help appreciate the complexity of early tooth morphogenesis. The present review surveys the data provided by computer-aided 3D analyses to update classical knowledge of early odontogenesis in the laboratory mouse and in humans. 3D reconstructions have demonstrated that odontogenesis in the early stages is a complex process which also includes the development of rudimentary odontogenic structures with different fates. Their developmental, evolutionary, and pathological aspects are discussed. The combination of in situ hybridization and 3D reconstruction have demonstrated the temporo-spatial dynamics of the signalling centres that reflect transient existence of rudimentary tooth primordia at loci where teeth were present in ancestors. The rudiments can rescue their suppressed development and revitalize, and then their subsequent autonomous development can give rise to oral pathologies. This shows that tooth-forming potential in mammals can be greater than that observed from their functional dentitions. From this perspective, the mouse rudimentary tooth primordia represent a natural model to test possibilities of tooth regeneration. © 2014 Australian Dental Association. KEYWORDS: 3D reconstruction; Tooth; development; human; mouse; odontogenesis

PMID 24495023


Expression of SHH signaling molecules in the developing human primary dentition

BMC Dev Biol. 2013 Apr 8;13:11. doi: 10.1186/1471-213X-13-11.

Hu X, Zhang S, Chen G, Lin C, Huang Z, Chen Y, Zhang Y. Source Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Science, Fujian Normal University, Fuzhou, Fujian, 350108, PR China. Abstract BACKGROUND: Our current knowledge on tooth development derives primarily from studies in mice. Very little is known about gene expression and function during human odontogenesis. Sonic Hedgehog (SHH) signaling has been demonstrated to play crucial roles in the development of multiple organs in mice, including the tooth. However, if SHH signaling molecules are expressed and function in the developing human embryonic tooth remain unknown. RESULTS: We conducted microarray assay to reveal the expression profile of SHH signaling pathway molecules. We then used in situ hybridization to validate and reveal spatial and temporal expression patterns of a number of selected molecules, including SHH, PTC1, SMO, GLI1, GLI2, and GLI3, in the developing human embryonic tooth germs, and compared them with that in mice. We found that all these genes exhibit similar but slightly distinct expression patterns in the human and mouse tooth germ at the cap and bell stages. CONCLUSIONS: Our results demonstrate the operation of active SHH signaling in the developing human tooth and suggest a conserved function of SHH signaling pathway during human odontogenesis.

PMID 23566240


Human Life History Evolution Explains Dissociation between the Timing of Tooth Eruption and Peak Rates of Root Growth

PLoS ONE 8(1): e54534.

Dean MC, Cole TJ (2013)

We explored the relationship between growth in tooth root length and the modern human extended period of childhood. Tooth roots provide support to counter chewing forces and so it is advantageous to grow roots quickly to allow teeth to erupt into function as early as possible. Growth in tooth root length occurs with a characteristic spurt or peak in rate sometime between tooth crown completion and root apex closure. Here we show that in Pan troglodytes the peak in root growth rate coincides with the period of time teeth are erupting into function. However, the timing of peak root velocity in modern humans occurs earlier than expected and coincides better with estimates for tooth eruption times in Homo erectus. With more time to grow longer roots prior to eruption and smaller teeth that now require less support at the time they come into function, the root growth spurt no longer confers any advantage in modern humans. We suggest that a prolonged life history schedule eventually neutralised this adaptation some time after the appearance of Homo erectus. The root spurt persists in modern humans as an intrinsic marker event that shows selection operated, not primarily on tooth tissue growth, but on the process of tooth eruption. This demonstrates the overarching influence of life history evolution on several aspects of dental development. These new insights into tooth root growth now provide an additional line of enquiry that may contribute to future studies of more recent life history and dietary adaptations within the genus Homo.


Genetic basis for tooth malformations: from mice to men and back again

Clin Genet. 2011 Aug 5. doi: 10.1111/j.1399-0004.2011.01762.x. [Epub ahead of print]

Mitsiadis T, Luder H. Source Institute of Oral Biology, Center of Dental Medicine, Faculty of Medicine, University of Zurich, 8032 Zurich, Switzerland.


Genetic basis for tooth malformations: from mice to men and back again. Teeth arise from sequential and reciprocal interactions between the oral epithelium and the cranial neural crest-derived mesenchyme. Their formation involves a precisely orchestrated series of molecular and morphogenetic events. Numerous regulatory genes that have been primarily found in organisms such as Drosophila, zebrafish, xenopus and mouse are associated with all stages of tooth formation (patterning, morphogenesis, cytodifferentiation and mineralization). Most of these genes belong to evolutionary conserved signaling pathways that regulate communication between epithelium and mesenchyme during embryonic development. These signaling molecules together with specific transcription factors constitute a unique molecular imprint for odontogenesis and contribute to the generation of teeth with various and function-specific shapes. Mutations in several genes involved in tooth formation cause developmental absence and/or defects of teeth in mice. In humans, the odontogenic molecular program is not as well known as that of mice. However, some insight can be obtained from the study of mutations in regulatory genes, which lead to tooth agenesis and/or the formation of defective dental tissues.

© 2011 John Wiley & Sons A/S.

PMID 21819395


Molecular genetics of tooth development

Curr Opin Genet Dev. 2009 Oct;19(5):504-10. Epub 2009 Oct 28.

Bei M.

Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston MA 02129, USA. Abstract Organogenesis depends upon a well-ordered series of inductive events involving coordination of molecular pathways that regulate the generation and patterning of specific cell types. Key questions in organogenesis involve the identification of the molecular mechanisms by which proteins interact to organize distinct pattern formation and cell fate determination. Tooth development is an excellent context for investigating this complex problem because of the wealth of information emerging from studies of model organisms and human mutations. Since there are no obvious sources of stem cells in adult human teeth, any attempt to create teeth de novo will probably require the reprogramming of other cell types. Thus, the fundamental understanding of the control mechanisms responsible for normal tooth patterning in the embryo will help us understand cell fate specificity and may provide valuable information towards tooth organ regeneration.

PMID 19875280

Human sex chromosomes in oral and craniofacial growth

Arch Oral Biol. 2009 Dec;54 Suppl 1:S18-24. Epub 2008 Jul 26.

Alvesalo L.

Institute of Dentistry, University of Oulu, Aapistie 3, FIN-90220 Oulu, Finland. Abstract Studies on tooth crown size and structure in families and in individuals with various sex chromosome anomalies have demonstrated differential direct effects of the human X and Y chromosome genes on growth. The Y chromosome promotes both tooth crown enamel and dentin growth, whereas the effect of the X chromosome on crown growth seems to be restricted to enamel formation. Enamel growth is decisively influenced by cell secretory function and dentin growth by cell proliferation. It is suggested that these differential effects of the X and Y chromosomes on growth explain the expression of sexual dimorphism in various somatic features. These include tooth crown and root size, crown shape and the number of the teeth, and under the assumption of genetic pleiotropy, torus mandibularis, statural growth, and sex ratio. It is of interest that molecular studies have shown that the gene loci for human amelogenin, the major protein component of the organic matrix in enamel are on both the X and Y chromosomes. Future questions include the role of the Y chromosome in the mineralization process, the concentric control of enamel and dentin growth, and gene expression.

PMID 18657798

Morphogenetic fields within the human dentition: a new, clinically relevant synthesis of an old concept

Arch Oral Biol. 2009 Dec;54 Suppl 1:S34-44. Epub 2008 Aug 29.

Townsend G, Harris EF, Lesot H, Clauss F, Brook A.

School of Dentistry, The University of Adelaide, Adelaide, South Australia 5005, Australia.


This paper reviews the concept of morphogenetic fields within the dentition that was first proposed by Butler (Butler PM. Studies of the mammalian dentition. Differentiation of the post-canine dentition. Proc Zool Soc Lond B 1939;109:1-36), then adapted for the human dentition by Dahlberg (Dahlberg AA. The changing dentition of man. J Am Dent Assoc 1945;32:676-90; Dahlberg AA. The dentition of the American Indian. In: Laughlin WS, editor. The Physical Anthropology of the American Indian. New York: Viking Fund Inc.; 1951. p. 138-76). The clone theory of dental development, proposed by Osborn (Osborn JW. Morphogenetic gradients: fields versus clones. In: Butler PM, Joysey KA, editors Development, function and evolution of teeth. London: Academic Press, 1978. p. 171-201), is then considered before these two important concepts are interpreted in the light of recent findings from molecular, cellular, genetic and theoretical and anthropological investigation. Sharpe (Sharpe PT. Homeobox genes and orofacial development. Connect Tissue Res 1995;32:17-25) put forward the concept of an odontogenic homeobox code to explain how different tooth classes are initiated in different parts of the oral cavity in response to molecular cues and the expression of specific groups of homeobox genes. Recently, Mitsiadis and Smith (Mitsiadis TA, Smith MM. How do genes make teeth to order through development? J Exp Zool (Mol Dev Evol) 2006; 306B:177-82.) proposed that the field, clone and homeobox code models could all be incorporated into a single model to explain dental patterning. We agree that these three models should be viewed as complementary rather than contradictory and propose that this unifying view can be extended into the clinical setting using findings on dental patterning in individuals with missing and extra teeth. The proposals are compatible with the unifying aetiological model developed by Brook (Brook AH. A unifying aetiological explanation for anomalies of tooth number and size. Archs Oral Biol 1984;29:373-78) based on human epidemiological and clinical findings. Indeed, this new synthesis can provide a sound foundation for clinical diagnosis, counselling and management of patients with various anomalies of dental development as well as suggesting hypotheses for future studies.

PMID 18760768

Controlling the number of tooth rows

Sci Signal. 2009 Aug 25;2(85):pe53.

Mikkola ML.

Institute of Biotechnology, University of Helsinki, Helsinki, Finland. Abstract The organization and renewal capacity of teeth vary greatly among vertebrates. Mammals have only one row of teeth that are renewed at most once, whereas many nonmammalian species have multirowed dentitions and show remarkable capacity to replace their teeth throughout life. Although knowledge on the genetic basis of tooth morphogenesis has increased exponentially over the past 20 years, little is known about the molecular mechanisms controlling sequential initiation of multiple tooth rows or restricting tooth development to one row in mammals. Mouse genetics has revealed a pivotal role for the transcription factor Osr2 in this process. Loss of Osr2 caused expansion of the expression domain of Bmp4, a well-known activator of tooth development, leading to the induction of supernumerary teeth in a manner resembling the initiation of a second tooth row in nonmammalian species.

PMID 19706870

Genetic basis of tooth agenesis

J Exp Zool B Mol Dev Evol. 2009 Jun 15;312B(4):320-42.

Nieminen P.

Institute of Dentistry, Biomedicum, University of Helsinki, Helsinki, Finland. Abstract Tooth agenesis or hypodontia, failure to develop all normally developing teeth, is one of the most common developmental anomalies in man. Common forms, including third molar agenesis and hypodontia of one or more of the incisors and premolars, constitute the great majority of cases. They typically affect those teeth that develop latest in each tooth class and these teeth are also most commonly affected in more severe and rare types of tooth agenesis. Specific vulnerability of the last developing teeth suggests that agenesis reflects quantitative defects during dental development. So far molecular genetics has revealed the genetic background of only rare forms of tooth agenesis. Mutations in MSX1, PAX9, AXIN2 and EDA have been identified in familial severe agenesis (oligodontia) and mutations in many other genes have been identified in syndromes in which tooth agenesis is a regular feature. Heterozygous loss of function mutations in many genes reduce the gene dose, whereas e.g. in hypohidrotic ectodermal dysplasia (EDA) the complete inactivation of the partially redundant signaling pathway reduces the signaling centers. Although these mechanisms involve quantitative disturbances, the phenotypes associated with mutations in different genes indicate that in addition to an overall reduction of odontogenic potential, tooth class-specific and more complex mechanisms are also involved. Although several of the genes so far identified in rare forms of tooth agenesis are being studied as candidate genes of common third molar agenesis and incisor and premolar hypodontia, it is plausible that novel genes that contribute to these phenotypes will also become identified.

(c) 2009 Wiley-Liss, Inc. PMID 19219933


Continuous tooth generation in mouse is induced by activated epithelial Wnt/beta-catenin signaling

Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18627-32. Epub 2006 Nov 22.

Järvinen E, Salazar-Ciudad I, Birchmeier W, Taketo MM, Jernvall J, Thesleff I.

Developmental Biology Program, Institute of Biotechnology, Viikki Biocenter, P.O. Box 56, University of Helsinki, FIN-00014 Helsinki, Finland.

Abstract The single replacement from milk teeth to permanent teeth makes mammalian teeth different from teeth of most nonmammalian vertebrates and other epithelial organs such as hair and feathers, whose continuous replacement has been linked to Wnt signaling. Here we show that mouse tooth buds expressing stabilized beta-catenin in epithelium give rise to dozens of teeth. The molar crowns, however, are typically simplified unicusped cones. We demonstrate that the supernumerary teeth develop by a renewal process where new signaling centers, the enamel knots, bud off from the existing dental epithelium. The basic aspects of the unlocked tooth renewal can be reproduced with a computer model on tooth development by increasing the intrinsic level of activator production, supporting the role of beta-catenin pathway as an upstream activator of enamel knot formation. These results may implicate Wnt signaling in tooth renewal, a capacity that was all but lost when mammals evolved progressively more complicated tooth shapes.

PMID 17121988

Cell fate determination during tooth development and regeneration.

"Teeth arise from sequential and reciprocal interactions between the oral epithelium and the underlying cranial neural crest-derived mesenchyme. Their formation involves a precisely orchestrated series of molecular and morphogenetic events, and gives us the opportunity to discover and understand the nature of the signals that direct cell fates and patterning. For that reason, it is important to elucidate how signaling factors work together in a defined number of cells to generate the diverse and precise patterned structures of the mature functional teeth. Over the last decade, substantial research efforts have been directed toward elucidating the molecular mechanisms that control cell fate decisions during tooth development. These efforts have contributed toward the increased knowledge on dental stem cells, and observation of the molecular similarities that exist between tooth development and regeneration."

Tooth Cells

Ameloblasts - Pre-ameloblasts differentiate from the inner enamel epithelium. Cells secrete enamel


Odontoblasts - neural crest-derived mesenchymal cells which differentiate under the influence of the enamel epithelium. Cells secrete dentin.

Epithelial Mesenchymal Interaction

  • local ectodermal thickening expresses several signaling molecules
  • these in turn signal to the underlying mesenchyme triggering mesenchymal condensation

(epithelially expressed Bmp4 induces Msx1 and Lef1 as well as itself in the underlying mesenchyme)

Four epithelial signaling molecules, Bmp2, Shh, Wnt10a, and Wnt10b, in the early inductive cascade, each signal has a distinct molecular action on the jaw mesenchyme.

Mouse (E11.0 and E12.0) - all four genes are specifically expressed in the epithelium.

Shh and Wnt10b induce general Hedgehog and Wnt targets, Ptc and Gli for Shh and Lef1 for Wnt10b,

Bmp2 is able to induce tooth-specific expression of Msx1.

(Text above modified from: Hélène R. Dassule and Andrew P. McMahon Developmental Biology, v 202, n 2, October 15, 1998, p215-227)

(More? [mechanism1.htm Developmental Mechanism - Epithelial Mesenchymal Interaction])

Periodontal Ligament (PDL)

The tooth is not anchored directly onto its bony socket (alveolar bone) but held in place by the periodontal ligament (PDL), a specialized connective tissue structure that surrounds the tooth root coating of cementum.

The additional roles of the PDL are to also act as; a shock absorber, transmitter of chewing forces (from tooth to bone), sensory information (heat, cold, pressure and pain).

The collagen fiber bundles within the ligament are called "Sharpey’s fibres".

Cementum (from investing layer of the dental follicle) is contiguous layer with the periodontal ligament on one surface and firmly adherent to dentine on the other surface.

(More? [skmus.htm Musculoskeletal Development])

Molecular Tooth Development

More than 300 genes have been associated with tooth development including: BMP4, FGF8, MSX1, MSX2, PAX9, PITX2, SHOX2, Delta/Notch, Hox-8, Runx2

Most recent review in Developmental Dynamics by Lin D, Huang Y, He F, Gu S, Zhang G, Chen Y, Zhang Y. Expression survey of genes critical for tooth development in the human embryonic tooth germ. Dev Dyn. 2007 Mar 29.

Amelogenin - abundant protein secreted by ameloblasts which is a major component of tooth enamel.

The papers below are from UNSW Embryology (version 3), information requires updating.

Bone Morphogenic Protein (BMP) / Fibroblast Growth Factor (FGF)

Growth factors in the BMP- and FGF-families are expressed in dental epithelium during initiation of tooth development and their effects on the underlying mesenchyme mimic those of the epithelium. They upregulate the expression of many genes, including the homeobox-containing Msx-1 and Msx-2, and stimulate cell proliferation suggesting that they may act as epithelial signals transmitting epithelial-mesenchymal interactions. During subsequent morphogenesis, when the characteristic shapes of individual teeth develop as a result from folding of the dental epithelium, several signal molecules including Sonic hedgehog, Bmps-2, 4, 7 and Fgf-4 are expressed specifically in restricted and transient epithelial cell clusters, called enamel knots.

(Text: Irma Thesleff and Carin Sahlberg Seminars in Cell & Developmental Biology, v 7, n 2, April, 1996, p185-193)


The expression pattern of Delta 1 in ameloblasts and odontoblasts is complementary to Notch1, Notch2, and Notch3 expression in adjacent epithelial and mesenchymal cells. Notch1 and Notch2 are upregulated in explants of dental mesenchyme adjacent to implanted cells expressing Delta1, suggesting that feedback regulation by Delta-Notch signaling ensures the spatial segregation of Notch receptors and ligands. TGF1 and BMPs induce Delta1 expression in dental mesenchyme explants at the stage at which Delta1 is upregulated in vivo, but not at earlier stages. In contrast to the Notch family receptors and their ligand Jagged1, expression of Delta1 in the tooth germ is not affected by epithelial-mesenchymal interactions, showing that the Notch receptors and their two ligands Jagged1 and Delta1 are subject to different regulations.

Text: Mitsiadis etal Developmental Biology,v 204, n 2, December 15, 1998, p420-431

<pubmed>17394220</pubmed> <pubmed>16632755</pubmed> <pubmed>16651263</pubmed> <pubmed>9520113</pubmed>


Dental Terms: ameloblast, amelogenin, amine fluoride (AmF), acidulated phosphate fluoride (APF), biomineralization, calcium phosphate (CaP), cementogenesis, dentoenamel junction (DEJ) decayed and filled primary teeth, decayed and filled surfaces on primary teeth, decayed, missing, and filled permanent teeth (DMF), decayed, missing, and filled surfaces on permanent teeth (DMFS), dentin sialophosphoprotein, enamel hypoplasia, ferric aluminum fluoride (FeAlF), periodontal ligament, sodium fluoride (NaF), stannous fluoride (SnF), titanium tetrafluoride (TiF).