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Published in final edited form as: J Struct Biol. 2024 Oct 9;216(4):108135. doi: 10.1016/j.jsb.2024.108135

The intricacies of tooth enamel: embryonic origin, development and human genetics

Olivier Duverger 1, Janice S Lee 1
PMCID: PMC11645192  NIHMSID: NIHMS2030435  PMID: 39384002

Abstract

Tooth enamel is a fascinating tissue with exceptional biomechanical properties that allow it to last for a lifetime. In this mini review, we discuss the unique embryonic origin of this highly mineralized tissue, the complex differentiation process that leads to its “construction” (amelogenesis), and the various genetic conditions that lead to impaired enamel development in humans (amelogenesis imperfecta). Tremendous progress was made in the last 30 years in understanding the molecular and cellular mechanism that leads to normal and pathologic enamel development. However, several aspects of amelogenesis remain to be elucidated and the function of many genes associated with amelogenesis imperfecta still needs to be decoded.

1). Introduction

Most organs in the human body form during embryonic and postnatal development, grow to their full size, and undergo variable degrees of remodeling with the ability to heal in response to injury over the course of our life, a capacity that decreases as we age1. This is however not the case for tooth enamel which is the outer surface that covers the crown of our teeth and is the only part of the tooth that is exposed to adversities of the oral cavity in a healthy dentition2. In pathological conditions or with age, gingival recession may result in the exposure of root dentin with increased sensitivity and susceptibility to root caries3. After our teeth erupt, the enamel that covers them is there for the entire life of the tooth (for primary teeth until they are shed, for permanent teeth until we lose them or until we die). Tooth enamel is the hardest tissue in the body with 96% of hydroxyapatite-like mineral phase (calcium phosphate lattice containing other ions such as carbonate, sodium, magnesium, potassium and fluoride), less than 1% of organic material and 3% of water4. However, enamel is more than just a highly mineralized tissue. The intricate ultrastructure of the tissue, as well as its fine mineral and organic composition, play a crucial role in providing exceptional biomechanical properties and resilience to chemical attack5–7. Tooth enamel is the product of an extremely sophisticated multistep differentiation process driven by a highly complex genetic program that serves to regulate both intracellular and extracellular interactions and processes during amelogenesis2.

In this mini review, after a brief comment on the unique embryonic origin of enamel and description of the differentiation process that leads to its formation, we will discuss the genetic diversity associated with anomalies of enamel formation in humans and give an overview of the large range of clinical conditions and protein functions related to enamel anomalies in the context of syndromes.

2). Tooth enamel: the only mineralized tissue produced by epithelial cells in humans

During human development, tooth enamel is derived from the dental epithelium, which makes it the only mineralized tissue that is produced by epithelial cells. All other mineralized tissues in the body (bone, dentin, cementum) are derived from connective tissues of mesodermal or neural crest origin. In vertebrates, the production of mineralized tissue by epithelial cells also applies to the development of enameloid at the surface of the scale in some fish species like the spotted gar, even though the development of this structure also involve mesodermal cells8,9. Enameloid is very similar to tooth enamel in structure and biomechanical properties10. In invertebrates, epithelial cells are also responsible for the formation of the exoskeleton of arthropods, as well as in the development of seashells. Nacre, which is the toughest seashell structure produced by bivalves, gastropods and cephalopods, exhibits biomechanical properties (stiffness, strength and toughness) that are very similar to those of enamel, although their ultrastructure and composition, both organic and mineral, are very different11. One common trait of all these epithelium-derived mineralized tissues is their high mineral content (over 95%), which is a level of mineralization that is not seen in any mesenchymal-derived mineralized tissues. Therefore, it appears that only epithelial cells can produce a mineralized tissue that reaches such extreme degree of mineralization as enamel, enameloid and nacre. This may in part be due to limited mineralization capacity for collagen-based connective tissues. Moreover, the barrier created by epithelia allows to isolate the tissue to be mineralized from its environment and the circulation, which is required to tightly control exchanges between compartments and create the perfect physico-chemical conditions for optimal mineralization.

3). Amelogenesis: building the hardest tissue in the body

The process of enamel formation is called amelogenesis2. It is driven by highly specialized cells derived from the dental epithelium and called ameloblast. These cells go through multiple stages, the three major ones being pre-secretion, secretion and maturation. The differentiation of ameloblasts happens at the interface between the dental epithelium and the dental mesenchyme that will form the dentin of the tooth and sends signals to the epithelium to initiate amelogenesis.

At the pre-secretion stage, pre-ameloblasts form during the initiation of dentin deposition on the mesenchymal side. Pre-ameloblasts become polarized between the underlying stratum intermedium, also derived from the dental epithelium, and the basement membrane that separates them form the mesenchyme and disappears when the odontoblasts deposit dentin (Figure 1A). At the secretion stage, ameloblasts acquire an elongated morphology with the development of a specialized structure, called the Tomes’ process, that will orchestrate the secretion of the enamel matrix at the apical end of the cell. At the same stage, the nuclei will accumulate at the opposite end of the cells, close to the stratum intermedium. It is during the secretion stage that ameloblasts deposit the enamel matrix, mainly composed of three major proteins (e.g., amelogenin, ameloblastin and enamelin) and deposited in the form of long rods separated by interrod enamel12,13. The secretion stage also comes with initiation of calcification, in the form of long thin ribbons of enamel mineral that will serve as a template for mature enamel (Figure 1A, lower left panel).

Figure 1. Development and structure of tooth enamel.

Figure 1.

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(A) Schematic representation and histological images of the three major stages of ameloblast development: pre-secretion, secretion and maturation. BM, basement membrane; Pre-Am, pre-ameloblasts; SI, stratum intermedium; En, enamel; TP, Tomes’ processes; Am, ameloblasts; R, rod; IR, interrod; PL, papillary layer, Od, odontoblasts. The lower panels are showing high resolution images of long and thin mineralized enamel ribbons produced during secretion (transmission electron microscopy) and fully mineralized enamel crystals formed after maturation is complete (scanning electron microscopy). (B) Schematic representation of the coordinated movement of ameloblasts that generates the decussation pattern of enamel rods during enamel secretion. This representation is typical of what would be seen in a section perpendicular to the growth axis of a rodent continuously growing incisor (cross section). As enamel is deposited, the enamel organ moves away from the matrix being deposited (black arrowheads). As this happens, ameloblasts in the yellow layer (front) move towards the right (black arrows facing right) while ameloblasts in the blue layer (back) move towards the left (black arrows facing left). This results in the decussation of enamel rods. (C) Scanning electron microscopy images of fractured enamel from mouse incisor (cross section). (D) Dolished and etched sections of enamel from mouse incisor (cross section). (E) Polished and etched sections of human enamel. Note the alternating orientation of the rods seen in enamel from mouse enamel, as represented in B. Rod decussation in human enamel involves bunches of rods as opposed to single rows of rods.

During the maturation stage, ameloblasts acquire a different morphology: they become shorter, lose their Tomes’ processes, and they are found in two alternating forms with smooth-ended and ruffle-ended ameloblasts (Figure 1A). At this stage, non-ameloblast dental cells form a highly vascularized papillary layer. During the maturation stage, the mission of ameloblasts is to (1) get rid of the majority of the enamel matrix proteins they previously secreted, in order to leave space for the full expansion of hydroxyapatite crystals14, (2) transfer all the minerals necessary for enamel maturation from the highly vascularized papillary layer to the enamel space, and (3) create the perfect chemical environment for optimal crystal formation2. In this context, the thin ribbons of enamel mineral grow in thickness and width to produce very dense and hard enamel (Figure 1A, lower right panel). At the end of the maturation stage, 96% of enamel is made of mineral, with only 1% of organic material remaining and about 3% of water.

Enamel is the most highly mineralized tissue in the body and other mineralized tissues fall far behind with 70% of hydroxyapatite. This level of mineralization contributes to making it the hardest tissue in the body. However, the exceptional biomechanical properties of enamel are also the result of an intricate arrangement of enamel rods established during the secretion stage. Enamel rods are not deposited parallel to one another or following a random pattern of apposition. Instead, they exhibit an intricate decussation pattern with adjacent rows or bundles of rods deposited in different orientations. This pattern is the result of a complex coordinated movement of ameloblasts during secretion15. This process is easier to conceptualize in the rodent continuously growing incisor in which rows of ameloblasts deposit enamel rods in alternating directions along the axis perpendicular to the main axis of the incisor (Figure 2, B–D). In human teeth, the decussation involves bundles of rod as opposed to rows (Figure 2E).

Figure 2. The genetics of amelogenesis imperfecta.

Figure 2.

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(A) Graphic representation of the constant increase in the number of genes associated with amelogenesis imperfecta (AI) since the first identification of mutations in the AMELX gene in patients with X-linked AI in 1991. The list of genes in which mutations were found in association with AI is indicated for each year. Genes associated with non-syndromic AI are shown in red and bold font. For genes that were associated to a syndrome before the amelogenesis imperfecta phenotype was included as a manifestation of the syndrome, the year of initial genetic characterization is indicated in parenthesis. The box on the right shows the same type of graph for dentinogenesis imperfecta (DGI) with a much lower number of genes and only one gene (DSPP) associated with non-syndromic DGI. (B) Classification of the genes associated with syndromic AI according to the top clinical conditions found in combination with enamel anomalies. Clinical conditions are sorted from the most frequently to the less frequently associated with AI: skeletal/craniofacial, neurological, cutaneous, ocular, cardiovascular, renal, hearing, immunologic and muscular. For each associated condition, the mutated genes are listed with a color palette indicating the function of the protein encoded by the gene. Genes with no color encode proteins of unknown function. The same color code was applied to the list of genes associated with non-syndromic AI, as shown in the box on the right. Organ icons in panel B were obtained on Biorender.com.

4). Human genetics: the long list of genes associated with amelogenesis imperfecta

Given the complexity of ameloblast differentiation and the multiple stages involved in the process, one can imagine that there are many steps along the way when things could go wrong. This is exemplified by the long list of genetic mutations that have been associated with enamel anomalies. Amelogenesis Imperfecta (AI) is the clinical term used to describe rare genetic diseases that affect the development of tooth enamel. It can be isolated (non-syndromic AI) or found in combination with other clinical conditions (syndromic AI)16,17, although the boundary between isolated and syndromic AI can sometimes be difficult to establish, which will be discussed later. AI can be caused by a reduction of the amount of enamel produced during secretion (hypoplastic AI) or by a reduction of the calcification level of enamel due to failure to either degrade the enamel matrix accumulated in the enamel space during secretion and/or promote full expansion of hydroxyapatite crystals during the maturation stage (hypomature/hypocalcified AI)18. Enamel development is also very sensitive to environmental disturbances (e.g., chemicals, stress) that will not be discussed here17,19.

Since the identification of mutations in the AMELX gene (encodes the most abundant enamel matrix protein, amelogenin) as the first characterized genetic cause of AI in 199120, the number of genes associated with AI has kept increasing. Figure 2A shows the increase in the number of genes associated with AI over the last thirty years, with indication of the genes identified each year. For details about each syndrome, the nature of the enamel anomalies observed and the associated clinical conditions, please refer to OMIM (i.e., Online Mendelian Inheritance in Man) and recent literature on the topic16,17. So far, at least eighty genes have been associated with AI, including sixteen associated with non-syndromic AI. This number contrasts significantly with the number of genes that have been associated with dentinogenesis imperfecta (DGI, anomalies of dentin formation) in the last forty years (Figure 2A, inset). Even though non-syndromic DGI exists in various forms in terms of the type of dentin anomalies presented by the patients, DSPP is so far the only gene that has been associated with non-syndromic DGI. The DSPP gene produces two major components of the dentin matrix, dentin sialoprotein (DSP) and dentin phosphoprotein (DPP), that can be affected in various ways depending on the position of the mutation in the DSPP gene21. DGI is also found in syndromic forms, essentially in combination with conditions that affect bone development, such as certain forms but not all forms of osteogenesis imperfecta. However, in the case of syndromic AI, enamel anomalies are found in combination with a broad range of clinical conditions, the most common ones being skeletal/craniofacial, neurological, cutaneous, ocular, cardiovascular, renal, hearing, immunologic and muscular disorders (Figure 2B). It is important to note that, in some cases, isolated/non-syndromic AI may not be as isolated as we think. This is true even for mutations in genes encoding proteins that are broadly considered to be “enamel-specific”. For example, even though enamel matrix proteins are most highly expressed by ameloblasts, they were recently shown to play a role in other tissues including bone22. On the other hand, it is interesting to see that mutations in widely expressed genes such as ITGB6 or SP6 can be associated with exclusive enamel phenotypes.

The functional diversity of the genes that are mutated in AI is also unique, with mutations found in genes encoding components of the extracellular matrix (ECM), cell adhesion molecules, transcription factors, cytoskeletal components, enzymes, solute/ion transporters, proteases, kinases, as well as proteins involved in cell signaling (ligands, receptors, transducers), calcium signaling, protein transport and DNA repair (Figure 2B). In contrast, genes mutated in DGI so far mostly encode components of the ECM (COL1A1, COL1A2, DSPP, SMOC2), regulators of the ECM (CRTAP, IFITM5), proteins affecting the biosynthesis, posttranslational modification or secretion of proteins (GALNT3, FKBP10, SERPINH1, TRIP11, MIA3), regulators of phosphate homeostasis (PHEX), or a transcription factor (DLX3) that was shown to control the expression of DSPP in odontoblasts23.

In the last thirty years, enamel research has significantly improved our understanding of the function of several of the genes mutated in AI2,16,17,24. We are highlighting some of these key findings below. It is well established that cell adhesion molecules play a crucial role in the attachment of pre-ameloblasts and ameloblasts to the basement membrane and the enamel matrix, respectively25. A tremendous effort has been invested in the study of the three major enamel matrix proteins (amelogenin, enamelin and ameloblastin) involved the formation of the complex structure of enamel12,13. The importance of their phosphorylation has also been well established26–29. The crucial role of the proteases MMP20 (expressed during secretion and maturation) and KLK4 (expressed during maturation only) in the processing and full degradation of enamel matrix proteins, which is essential for the maturation of enamel, is also well established30–32. Even though the secretion of enamel matrix proteins is limited during the maturation stage, some of them such as amelotin (encoded by AMTN) and ODAM (encoded by ODAM) were shown to play a role in enamel mineralization33,34. The importance of a tight regulation the pH during the process of maturation in order to create and optimal environment for crystal growth during maturation is well understood, and the involvement of solute and ion transporter (SLCs) in this process is undeniable35,36. The crucial role played by tight junctions (CLDNs) in the control of the transepithelial transfer of ions across the enamel organ has also been demonstrated37. The importance of tight regulation of calcium signaling via ORAI1 and STIM1 in maturation-stage ameloblasts has also been validated38. For some of the transcription factors associated with AI (DLX3, SP6), downstream target in ameloblasts have been identified and correlated to the enamel defects observed39,40. Interestingly, a recent study found that the transcription factor AIRE which is mutated in an autoimmune disease (Autoimmune polyendocrinopathy syndrome, type I) that exhibits AI, is not expressed in ameloblasts but in the thymus were its absence results in increased production of autoantibodies targeting several ameloblast-specific proteins (AMELX, AMBN, ACP4)41. Despite these tremendous advances, several aspects of amelogenesis still remain to be elucidated. This includes the mechanism that drives the process of enamel rod decussation. Even though there are indications that the remodeling of cell-cell interactions via proteases as well as cytoskeletal remodeling via myosin II activity are involved15,42–44, it is still not clear how the coordinated movement of ameloblasts is regulated during enamel secretion. Another aspect of amelogenesis that would require more attention is the involvement of the stratum intermedium and the papillary layer that constitute essential supporting tissues for the ameloblasts during secretion and maturation, respectively.

Of note, for several syndromic forms of AI, the enamel phenotype was described and included as a clinical feature of the disease only several years after the initial characterization of the syndrome and the identification of the mutation that causes it (Fig. 2A). For example, although mutations in CLDN16 and CLDN19 were identified as the cause of two forms of renal hypomagnesemia in 1999 and 200645,46, respectively, the amelogenesis imperfecta phenotype associated with these diseases was only reported in 2016 and 2017, respectively37,47. The same is true for the AI phenotype in Costello syndrome described only nine years after HRAS mutations were associated with the disease48, the AI phenotype in hypophosphatasia described eight years after ALPL mutations were identified49, the AI phenotype in Raine syndrome described four years after mutations in FAM20C were reported50. In the case of Loeys-Dietz syndrome (LDS), a connective tissue disorder characterized by aortic aneurysm and craniofacial anomalies and caused by mutations in genes involved in TGF-β signaling (TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, SMAD3), a primer for diagnosis and management published in 2014 included the following statement: “Anecdotally, many individuals present with decreased dental enamel, causing significant damage of primary teeth requiring extraction”51. However, until more recently, this was the only mention of this phenotype that was not included as a trait of the syndrome. It is only in 2020, 15 years after the genetic etiology of LDS was determined, that thorough dental-oral evaluations in LDS concluded that severe enamel anomalies were mostly seen in patients with LDS Type 2, caused by mutations in the TGFBR2 gene52. The AI phenotype in LDS Type 2 was confirmed in a more recent report16.

This delay in the identification of AI in rare syndromes is an indication that enamel anomalies, and dental anomalies in general, are often overlooked compared to more life-threatening conditions associated with the diseases. It is common for these anomalies to be seen as a consequence of lifestyle, oral hygiene or medication, rather than developmental anomalies directly associated with the disease. Therefore, there is probably still a large number of syndromes for which enamel anomalies remain to be reported and characterized.

5). Conclusion

Enamel is a unique mineralized tissue that is built to last for years through a complex differentiation process. The large number of genes associated with syndromic and non-syndromic AI is a clear reflection of the complexity of the process of enamel development. Although research in the last 30 years have significantly improved our understanding of the cellular and molecular mechanism that leads to enamel formation, a large proportion of the genes mutated in AI encode proteins for which the function in enamel development remains unknown, especially for those associated with syndromic AI.

Acknowledgments

This work was supported by the Intramural Research Program of the NIH, NIDCR.

Footnotes

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