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Human Molecular Genetics, 2003, Vol. 12, Review Issue 1 R69-R73
DOI: 10.1093/hmg/ddg085
© 2003 Oxford University Press

Normal and abnormal dental development

Isabelle Miletich and Paul T. Sharpe*

Department of Craniofacial Development, GKT Dental Institute, King's College London, Guy's Hospital, London Bridge, London SE1 9RT, UK

Received January 8, 2003; Accepted February 5, 2003


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 GENETIC DEFECTS AFFECTING ALL...
 PATTERNING DEFECTS
 REFERENCES
 
Teeth are vertebrate organs that arise from complex and progressive interactions between an ectoderm, the oral epithelium and an underlying mesenchyme. During their early development, tooth germs exhibit many morphological and molecular similarities with other developing epithelial appendages, such as hair follicles, mammary and salivary glands, lungs, kidneys, etc. The developing mouse tooth germ, which is an experimentally accessible model for organogenesis, provides a powerful tool for elucidating the molecular mechanisms that control the development of these organs. Dentition patterning also provides a unique model for understanding how different shapes of teeth arise in different regions of the jaws. We review here the main signalling networks mediating the epithelial–mesenchymal interactions involved in tooth morphogenesis and patterning.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
GENETIC DEFECTS AFFECTING ALL...
 PATTERNING DEFECTS
 REFERENCES
 
Murine tooth development has proved to be a powerful model to study the genetics and molecular mechanisms of mammalian tooth development. Mouse dentition, however, differs significantly from human dentition. Mice only develop two different tooth shapes, three molars proximally and one incisor distally on each side on the jaws. The region of the jaw where humans develop canines and premolars, between incisors and molars, is a region devoid of teeth in mice, called the diastema. In addition, mice only have one set of teeth while humans have two, one deciduous (milk teeth) and one permanent. Significantly, permanent teeth are those predominantly affected in human hypodontia (agenesis of six or more teeth), which is a common human anomaly affecting up to 20% of the population.

Embryonic development of teeth relies on a series of reciprocal inductive signallings between two adjacent tissues, an epithelium and a mesenchyme. Separation and recombination of these two tissues in mice has shown that odontogenesis is induced by the epithelium around embryonic day 10 and two days later the odontogenic potential switches to the mesenchyme (1,2). The mesenchymal cells participating in tooth development form from cranial neural crest (CNC) cells, which delaminate at the junction between the extreme dorsal surface of the neural tube and the ectoderm, and migrate extensively to populate the branchial arches (BA). Any CNC cell population can support tooth development when recombined with oral ectoderm (2). In contrast to the posteriorly located BA and main body axis, the first BA (BA1), from which the mandible and the proximal maxilla develop, does not express Hox genes and tooth development is controlled by local interactions involving non-Hox homeobox and other transcriptional regulators (3).

Whatever the final shape of the tooth, early steps of tooth development in mammals are very similar. At embryonic days 9–11, the oral epithelium initiates tooth development by signalling through generic molecules including FGFs (Fibroblast Growth Factors), BMPs (Bone Morphogenetic Proteins), Wnts and Shh (Sonic hedgehog) to the underlying neural crest-derived mesenchyme. These early molecular events are accompanied by localized thickenings of the oral epithelium at the position of the future teeth (Fig. 1). The so-called ‘dental lamina’ grows and buds into the BA mesenchyme, at the sites of tooth formation, under the control of reciprocal signals induced in the mesenchyme. Re-use of the BMP and FGF signalling cascades together with other signals such as activinßA is implicated in the regulation of tooth bud formation, which is accompanied by mesenchymal cell condensation around the tooth germs. The next stage of tooth development marks the onset of the development of the tooth crown and acquisition of tooth shape. The tip of the epithelial tooth bud folds, resulting in the formation of a cap-like structure which surrounds condensed mesenchyme referred to as ‘dental papilla’. Subsequent folding and growth of the epithelial cap eventually gives rise to the bell stage. These last two stages are characterized by the appearance of two sets of transient epithelial signalling centres. They are restricted subsets of epithelial cells which express many of the same signals as the early epithelial ones, and regulate cusp morphogenesis by controlling cell proliferation and apoptosis (4). The enamel knot appears at the tip of the tooth bud, where the first epithelial folding occurs (Fig. 1). Molar teeth develop a second set of signalling centres at the sites of cusp formation, the ‘secondary enamel knots’, which determine the multicuspid pattern of molar crowns.



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  		Figure 1. Schematic representation of molar tooth development. Genes essential for tooth development are indicated at the developmental stage at which tooth development arrests in mutant mice. They are highlighted in yellow, blue or red, depending on their requirement, respectively, in the epithelium, mesenchyme or enamel knot. Red arrows represent the reciprocal signalling between epithelium and mesenchyme during advancing tooth development. At the bell stage, the two rows of developing ameloblasts and odontoblasts are respectively indicated as bright yellow and dark blue lines at the epitheliomesenchymal surface. Am, ameloblasts, Cm, condensed mesenchyme, Dp, dental papilla; Ek, enamel knot; Ep, epithelium; Mes, mesenchyme, Od, odontoblasts; Sek, secondary enamel knot.

 

   GENETIC DEFECTS AFFECTING ALL TEETH
TOP
 ABSTRACT
 INTRODUCTION
 GENETIC DEFECTS AFFECTING ALL...
PATTERNING DEFECTS
 REFERENCES
 
Wnt/Lef1 and FGF signalling
The canonical Wnt signals play an essential role during tooth development. Either blocking Wnt co-receptors or knocking-out Lef1, a nuclear mediator of Wnt signalling, lead to an absence of all teeth. Dickkopf1 (Dkk1) is a potent and specific secreted inhibitor of Wnt action, which functions by binding and inhibiting lipoprotein receptor-related protein (LRP) coreceptors required for activation of the canonical Wnt signalling pathway. Transgenic mice expressing Dkk1 in basal epidermal cells (which is likely to diffuse to the adjacent epithelial and mesenchymal cells), exhibit tooth development arrested at the epithelial thickening stage (5). Wnt genes -4, -6, -10a and -10b, which are expressed in the presumptive dental epithelium at this stage, are likely candidates for these Wnt signals involved in the dental lamina to bud stage transition (6,7). Binding of Wnts to their receptors causes formation in the nucleus of active transcription complexes between ß-catenin and Lef1, a member of the LEF/TCF family of DNA binding proteins, that activates Wnt target gene expression. Lef1 null mice have tooth development arrested at the bud stage, although the requirement for Lef1 may be earlier when it is expressed in the epithelium (8), suggesting that Wnt signalling is also required for the bud-to-cap transition (9). The fact that tooth development arrests earlier in Dkk1 mice than Lef1 null mice may be due to redundancy of Lef1 with other LEF/TCF family members. At the bud stage, Lef1 is required transiently in the epithelium to generate an inductive signal to the mesenchyme, triggering the formation of the dental papilla (8). Epithelial Fgf4 has been identified as a Lef1 direct target, which in turn induces mesenchymal FGF expression, which is required for Shh epithelial expression in the future enamel knot (10). Epithelial FGF signalling is also required for tooth development as mice deficient for the FGF receptor Fgfr2(IIIb), which is expressed in the epithelium, fail to develop teeth beyond the bud stage (11).

Pax9 and Msx1: inductive potential to the mesenchyme
Pax9, a member of the paired-box family of transcription factors, is a key regulator during tooth development. Pax9 expression is restricted to prospective tooth mesenchyme at the bud stage, marking the sites of future tooth formation (12). In Pax9-deficient embryos, odontogenesis is arrested at the bud stage, and other genes exhibiting overlapping expression pattern with Pax9 in the dental mesenchyme, such as Bmp4, Msx1 and Lef1, are downregulated in Pax9-/- tooth bud mesenchyme, suggesting that Pax9 acts upstream of these genes (13). In Msx1-/- and Lef1-/- embryos, teeth are also arrested at the bud-to-cap transition (9,14,15). Further regulatory hierarchy places Bmp4 upstream of Msx1, since either exogenous Bmp4 (16,17), or expression of a Bmp4 transgene driven by the Msx1 promoter (18), can rescue Msx1-/- tooth arrest. Surprisingly, down-regulation of Bmp4 and Lef1 are observed in Msx1-/- mesenchyme (17), pointing out these two genes as Msx1 targets. A positive feedback loop between Msx1 and Bmp4 is a likely explanation. In Msx1 mutants, loss of Bmp4 signalling from mesenchyme to epithelium (due to loss of Msx1) would account for Lef1 (a Bmp4 target) downregulation. Dominantly inherited mutations in human PAX9 and MSX1 genes have also been identified as causes for missing teeth in man mainly involving posterior teeth. Mutation of human PAX9 causes agenesis of most permanent molars (19), and deletion of the entire PAX9 gene has recently been involved in agenesis of all primary and permanent molars (20). Other studies have associated human MSX1 mutations with agenesis of the second premolars and third molars (wisdom teeth) (21–23). Functional redundancy clearly plays an important part in tooth development. For example, whereas mice lacking Msx2 have a defect in tooth mineralization due to ameloblast degeneration (24), and mice lacking Msx1 have teeth arrested at the bud stage (14), Msx1, Msx2 double mutants have tooth development arrested at the thickening stage (25).

Gli transcription factors
The three mouse Gli zinc finger transcription factors (Gli1, Gli2 and Gli3) are the homologues of Drosophila Cubitus interruptus (Ci), which activates the transcription of target genes of the Hedgehog (Hh) pathway. From the epithelial thickening stage, the Gli genes are coexpressed in the epithelium and the mesenchyme, while Shh expression is highly restricted to the epithelium (26). In Gli2-/- embryos, maxillary incisors are fused, probably due to abnormal midfacial development, a common feature associated with defects in the Shh signalling pathway. Despite Gli3 mutants displaying no obvious tooth abnormality, Gli2-/- tooth defects worsen in a Gli3-/- context. Gli2-/-; Gli3-/- mutants have development of both molars and incisors arrested at a rudimentary bud stage, and single, fused incisor tooth germs are detected, which are reminiscent of the Gli2-/- phenotype (26). The Gli2 and Gli3 genes thus appear to be functionally redundant for tooth development. Interestingly, Gli2-/-; Gli3+/- mice exhibit an intermediate phenotype, with teeth of small size. Another study using a conditional allele of Shh, in which Shh activity is removed from the dental epithelium at the bud stage, also leads to teeth of reduced size (27), pointing out an essential role for Shh in tooth growth.

p63
The p63 (TP73L) gene has been shown to be critical for epithelial stem cells to maintain their proliferative capacity and self-renew (28). Mice mutant for p63 exhibit pleiotropic defects due to the failure to maintain or develop stratified epithelia. Odontogenesis, which is initiated by signals from the epithelium to the neural crest derived-mesenchyme, is thus severely impaired, leading to a complete absence of tooth primordia. Mutations in the human p63 gene have been associated with several syndromes including various tooth abnormalities ranging from enamel dysplasia to a loss of teeth which can affect both primary and permanent dentitions (29).

Pitx2
Pitx2, a bicoid-related transcription factor, is first expressed in presumptive dental epithelium, becomes localized to tooth epithelial thickenings, and shifts at the bud stage to being expressed in the condensing mesenchyme. Pitx2-/- mice have tooth development arrested at the bud stage (30).

Runx2, Sp3 and Shh: terminal cytodifferentiation
During the bell stage, differentiation of two tooth-specific cell types occurs along the epitheliomesenchymal interface of tooth germs (Fig. 1). The odontoblasts (dentin-forming cells) differentiate from the mesenchyme of the dental papilla, and the ameloblasts (enamel-forming cells) differentiate from the epithelial component of the tooth germ, giving rise to two rows of elongated, polarized cells, facing each other and progressively retreating away from each other as the thickness of dentin and enamel increases. Odontoblast differentiation occurs first, and the secretion of the first layer of predentine matrix triggers the terminal differentiation of preameloblasts.

The transcription factor Runx2 (also called Cbfa1), known for its critical role in osteoblast differentiation, has been recently shown also to take part in the signalling networks regulating tooth development. Lack of Runx2 allows tooth development to proceed up to the cap/bell stage (31), while earlier tooth arrests have been reported for any other mutations blocking tooth development. Runx2-/- bell stage tooth germs are hypoplastic, and in newborn incisors, that exhibit a less severe phenotype than molars (certainly due to their earlier development), cytodifferentiation of the two tooth specialized cell types is severely impaired, leading to abnormal dentin and absence of enamel. Heterozygous loss of RUNX2 in humans causes cleidocranial dysplasia, a syndrome characterized by extensive skeletal defects, which are associated with supernumerary teeth developing with the permanent dentition (32). Runx2-/- mice do not develop extra teeth, which may be due to the fact that mice only have one set of teeth. Abnormal extra epithelial buddings (which could possibly lead to extra teeth) are however visible at tooth arrest in Runx2-/- embryos, in addition to the regular epithelial foldings leading to cuspal morphogenesis. The Sp3 transcription factor (Specificity Protein 3, one member of a family of four Sp proteins) is also involved in tooth cytodifferentiation, as mice deficient for Sp3 exhibit complete lack of enamel due to lack of ameloblast-specific transcripts (33). Sp3 could function as a regulator of ameloblast-specific genes. Removal of Shh signalling from the dental epithelium (via removal of the activity of the Smoothened membrane protein, that is essential for transduction of the Shh signal) also disrupts ameloblast differentiation (34).


   PATTERNING DEFECTS
TOP
 ABSTRACT
 INTRODUCTION
 GENETIC DEFECTS AFFECTING ALL...
 PATTERNING DEFECTS
REFERENCES
 
Mandibular and maxillary molars
Activin is a member of the TGFß family of growth factors. Activin proteins function as dimers consisting of ßA and ßB subunits encoded respectively by the activinßA (Inhba) and activinßB (Inhbb) genes. ActivinßA expression is localized in presumptive tooth mesenchyme of all teeth where it acts as an early mesenchymal to epithelial signal. In newborn activinßA mutant mice, all teeth are lacking, except maxillary molars, which exhibit normal development (35). Surprisingly, in activinßA mutants, activin target gene expression is downregulated in the dental epithelium of all tooth germs, including maxillary molars. This indicates that another TGFß-like signalling molecule is unlikely to compensate for the loss of activinßA activity in maxillary molars. Mutations in Dlx1 and Dlx2 result in the reciprocal phenotype to activinßA mutants: all maxillary molar teeth are absent whilst the other teeth develop normally (36). Dlx genes are homeobox genes physically linked as pairs (Dlx2/1, Dlx5/6 and Dlx3/7), which share regulatory elements and thus display similar expression patterns. In mice, only Dlx1 and -2 are expressed in the developing maxillary arch, whilst Dlx1–6 are expressed in overlapping domains in the mandibular primordia. Functional redundancy of Dlx genes in the mandible could account for normal development of mandibular molars in the absence of Dlx1/2. Both maxillary and mandibular molars, together with most BA1-derived structures, are absent in mice in which Fgf8 is inactivated in the ectoderm of the nascent BA1, while incisors, which develop from the most distal region, are not affected (37).

Transformation of tooth type
Several homeobox genes, namely Msx1/2, Dlx1–6 and Barx1, show spatially restricted expression in the mesenchyme of BA1 before any morphological sign of tooth development. Broader than the territories where teeth will develop, these expression domains have been proposed to define competency territories governing dental patterning along the proximodostal axis. The odontogenic homeobox code model (38) proposes that specific combinations of homeobox gene expression in the future tooth mesenchyme lead to different types of teeth: multicuspid teeth (molars) proximally, and monocuspid teeth (canines and incisors) distally. Strong support for this model comes from transformation of tooth identity from incisor to molar by distal expansion of Barx1 expression, which is normally restricted to the proximal (molar) mesenchyme (39). The distal epithelium secretes BMP4 which both induces Msx1 gene expression and represses Barx1 expression in the underlying mesenchyme. Implantation in the distal mesenchyme of Noggin beads (a BMP antagonist) antagonizes these two roles and results in the incisor–molar transformation. It is not clear if loss of Msx1 expression is required together with ectopic Barx1 expression for tooth transformation.

Generation of extra teeth
Tissue recombination experiments between Lef1-/- and normal tissues have shown that Lef1 is only required in the epithelium to allow normal tooth development (8). Surprisingly, upregulation of Lef1 in the mouse oral epithelium triggers formation of abnormal invaginations of the epithelium in the mesenchyme, which is correlated with the finding of hairs and tooth-like structures positioned at inappropriate sites on the mouth gums (40).

Cusp defects
The tumor necrosis factor (TNF) signalling pathway is an important regulator of tooth germ epithelial morphogenesis, which establishes tooth shape and particularly the typical cusp/depression pattern of the molar crown. In mouse, the Tabby (Ta) gene encodes the soluble TNF ligand ectodysplasin (Eda), which binds to the TNF receptor (Edar), encoded by the downless (dl ) gene, leading to activation of NF-{kappa}B via the cytoplasmic death domain adapter Edaradd, encoded by the crinkled (Cr) locus. Adult mice bearing mutations in the Ta, dl or Cr genes display an ectodermal dysplasia phenotype, which is characterized by the abnormal development of ectoderm-derived structures such as teeth. Tooth abnormalities mainly affect molars, which are reduced in size and have a flattened appearance, as a result of very shallow depressions between the cusps (41–43). These phenotypes have been related to enamel knot defects at the bud stage: in dl mutant embryos, the restricted epithelial compartment of the enamel knot fails to form, and enamel knot cells end up as a sheet called the ‘enamel rope’ (43), whereas in Ta mutants the enamel knot has a normal shape but is smaller (42). At the bud stage, Edar and Eda have complementary epithelial expression domains: Edar is expressed at the tip of the bud, where the signalling centre forms, whilst Eda is expressed in the outer tooth germ epithelium. Although TNF signalling occurs exclusively in tooth germ epithelium, Edar expression is regulated by the mesenchymal activin-ßA whilst Eda expression is under control of the Wnt/ß-catenin/Lef1 signalling pathway (44). Mutations in the human EDA1 (45), EDAR (46) and EDARADD (41) genes (all three responsible for hypohidrotic ectodermal dysplasia) often result in more severe phenotypes than their mouse counterparts, resulting in tooth loss and malformations (47).


   FOOTNOTES
 
* To whom correspondence should be addressed. Email: paul.sharpe{at}kcl.ac.uk Back


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 ABSTRACT
 INTRODUCTION
 GENETIC DEFECTS AFFECTING ALL...
 PATTERNING DEFECTS
 REFERENCES
 

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