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Review Article |
Department of Craniofacial Development, G. K. T. Dental Institute, King's College London, London Bridge, London SE1 9RT, U.K.
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Introduction |
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 Top Introduction An Overview of OdontogenesisPatterning of the DentitionHomeobox GenesEpithelial-mesenchymal...The Role of the...Clinical PerspectivesConclusionsReferences |
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), the mechanisms that
are involved at a molecular level are only now beginning to be elucidated (Maas and
Bei, 1997). This is largely due to the revolution in molecular biological techniques
that has occurred over the last decade and their continued application in developmental biology.
It is the mouse that has become the principle organism used to study mammalian development
because of its suitability for both genetic and embryological manipulation (Ignelzi et al., 1995). Engineered genes can be permanently inserted into the
germline to produce transgenic mice which allows a direct method of studying the function of a
gene during development. Similarly, gene targeting experiments can produce selective gene
knockout and transgenic mice that are missing the expression of specific genes. As these
techniques of introducing DNA into the cell have become more sophisticated, the generation of
transgenic mice using reporter gene constructs are now beginning to provide information on the
regulatory sequences that are involved in controlling the transcription of particular genes.
Fundamental to the study of tooth development is the manipulation of tooth germ explants from wild type and mutant mice. These explants can be cultured in vitro as far as odontoblast and ameloblast differentiation with the early stages of both dentine and enamel secretion beginning to occur (Figure 1). The technique of in situ hybridization, using labelled mRNA probes allows the domains of expression of specific genes to be visualized in these developing tooth germs. Cultured tooth germs can now be transferred into the kidney capsules of adult male mice, allowing tooth development to proceed to full crown formation and localized alveolar bone differentiation (Figure 2). Further adaptations to the culture technique have provided great insight into the signalling mechanisms that occur during odontogenesis. Dental epithelium and mesenchyme can be separated, and recombined with tissues of different origins, developmental stages, and altered genetic constitutions. Agarose or heparin acrylic beads expressing protein signalling molecules, and growth factors can be implanted into cultured epithelium and mesenchyme. The resulting effects of these techniques on downstream gene expression and odontogenic phenotype can be then be evaluated. This article aims to give an overview of the more established theories on the molecular regulation of tooth development and to introduce some recent advances that have occurred in this ever expanding field.
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An Overview of Odontogenesis |
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TopIntroductionAn Overview of OdontogenesisPatterning of the DentitionHomeobox GenesEpithelial-mesenchymal...The Role of the...Clinical PerspectivesConclusionsReferences |
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At the late bell stage of development, the innermost layer of cells of the enamel organ, the inner enamel epithelium, induce those adjacent cells of the dental papilla to differentiate into odontoblasts. Odontoblasts are responsible for the formation and mineralization of the dentine matrix. Dentine formation is preceded by the formation of predentine. The first layer of predentine acts as a signal to the overlying inner enamel epithelial cells to differentiate into ameloblasts and begin secreting the enamel matrix. At the margins of the enamel organ the cells of the inner enamel epithelium are confluent with the outer enamel epithelial cells at the cervical loop. Growth of these cells in an apical direction forms a skirt-like sheet of cells, Hertwig's epithelial root sheath, which maps out the future root morphology of the developing tooth and induces the further differentiation of odontoblasts. Degeneration of this root sheath leads to the exposure of the cells of the dental follicle to the newly-formed root dentine. This induces the differentiation of these mesenchymal cells into cementoblasts which begin to deposit cementum onto the root surface. Surrounding the enamel organ, the cells of the dental follicle produce the alveolar bone and collagen fibres of the periodontium. The developing tooth remains housed in this cavity of alveolar bone until the process of eruption begins.
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Patterning of the Dentition |
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TopIntroductionAn Overview of OdontogenesisPatterning of the DentitionHomeobox GenesEpithelial-mesenchymal...The Role of the...Clinical PerspectivesConclusionsReferences |
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) suggests that all tooth primordia are
initially equivalent, with the individual shapes that they subsequently develop into being
controlled by varying concentrations of morphogens in the local environment. A number of
diffusible signalling molecules have been identified that may be involved in
concentration-dependant, threshold response mechanisms which could produce periodicity along
the developing dental axes. However, if these mechanisms are responsible for patterning in both
dentitions then they must act very early on in the developmental process. Unlike the mandibular
dental axis the developing maxillary dentition is not continuous. The maxillary incisors develop
in the medial nasal processes, whilst the remainder of the dentition develops in the maxillary
processes of the first arch (Weiss et al., 1998).
In the clonal model (Osborn, 1978), the tooth primordia are said to be
prespecified with each migrating cell population being equipped with the necessary positional
information to produce the different classes of teeth from inception. Much attention has been
given to neural crest cells, a transient embryonic cell population that arises from the lateral
margins of the neural plate during neurulation. Migration of these cells from the region of the
developing hindbrain provides much of the mesenchyme (ectomesenchyme) of the developing
oro-facial region, including that contributing to odontogenesis (Noden, 1984). A key question in understanding how the developing teeth are initiated and
patterned is to know the extent to which neural crest cells are prespecified prior to their
migration. A number of different genes have emerged that are strong candidates for controlling
neural crest prespecification.
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Homeobox Genes |
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TopIntroductionAn Overview of OdontogenesisPatterning of the DentitionHomeobox GenesEpithelial-mesenchymal...The Role of the...Clinical PerspectivesConclusionsReferences |
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). The homeobox was originally discovered in the homeotic selector genes of
the fruitfly Drosophila melanogaster, where they are responsible for specifying segment
identity in the developing fly. Homeotic genes exhibit a feature known as co-linearity, their
spatial arrangement along the chromosome is in the same order as their patterns of expression
along the anteroposterior axis of the fly embryo (Lewis, 1978). Genes
expressed at the 3' end of the complex are expressed anteriorly, whereas those at the
5' end are expressed posteriorly. Thus, each segment of the fly has a different
combination of homeotic gene expression that specifies the individuality of that segment.
Mutations in these genes can lead to bizarre homeotic transformations where one segment of the
fly can be transformed into another segment. As an example, the antennapedia gene specifies
identity of the second thoracic segment, in the dominant mutation of antennapedia this gene is
also expressed in the head. The result of this is the growth of legs from the head sockets instead
of antennae. Cross-hybridization studies have shown that the homeobox is not just confined to
insects, it has been conserved during evolution and is also found in vertebrates (McGinnis et al., 1984b). The equivalent family of vertebrate genes are the
Hox genes and these, too, express co-linearity. Both in mice and man, four Hox gene clusters are
found on four different chromosomes.
The hindbrain region of the developing neural tube from which the neural crest migrates is
segmented into eight rhombomeres. Segment specific combinatorial Hox gene expression
specifies each rhombomeres identity. The migrating neural crest carries this Hox code defined
patterning which is transferred to the branchial arches (Lumsden et al., 1991). The Hoxcode thus sets up regional diversity within the branchial arch system. It is
plausible, therefore, that the Hox code of those cells migrating to the tooth forming regions is
responsible for specifying and patterning the dentition. However, the Hox genes are not
expressed in regions rostral to rhombomere 2 which means that no Hox gene expression is seen
in the neural crest that migrates to the craniofacial region, including the first branchial arch (Hunt et al., 1991a,b). In terms of
patterning tooth development, we have to look at a subfamily of homeobox genes that do show
temporal and spatial patterns of expression within the first branchial arch.
Msx and Dlx Homeobox Genes
Two classes of homeobox genes, the Msx and Dlx genes are expressed in both migrating neural
crest cells and in spatially restricted regions of the first branchial arch during murine
development. These genes also contain a highly conserved homeobox, but it is more divergent
than the Hox and homeotic genes. The vertebrate Msx genes are a three-gene family related to
the Drosophila gene muscle-segment homeobox (msh) (Bell et
al., 1993). The Dlx genes have also been conserved during evolution
and bear homology to the distal-less gene of Drosophila (Porteus et al., 1991).
Prior to the initiation of odontogenesis both Msx-1 and Msx-2 exhibit very specific
horseshoe-shaped fields of corresponding mesenchymal expression in the anterior regions of the
first arch (MacKenzie et al., 1992). These expression patterns
are coincident except along their posterior border where the expression of Msx-1 extends further
than Msx-2. This region of isolated mesenchymal Msx-1 expression corresponds to the position
of the future primary epithelial thickening. As tooth development progresses the expression of
Msx-1 becomes localized in the mesenchymal cells of the dental follicle and papilla. The
domains of expression of Msx-2 also become more restricted to the dental follicle and papilla,
but unlike Msx-1, Msx-2 is also expressed strongly in the enamel organ (Figure 3). In contrast, the expression of Dlx-1 and Dlx-2 in the maxillary and mandibular
arch mesenchyme is restricted to the proximal regions where the future molar teeth will develop.
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). Prior to the appearance of the primary epithelial thickening Barx-1 (along
with Dlx-2) is expressed in the posterior regions of the first branchial arch mesenchyme, the
region of future molar development. There is no Barx-1 expression in the anterior regions. As
tooth development proceeds, Barx-1 expression becomes localized exclusively to the
mesenchymal regions around the developing molars (Tissier-Seta et al.,
1995; Thomas and Sharpe, 1998).
An Odontogenic Homeobox Code
Based upon such highly specific domains of expression, it has been suggested that these genes
provide a homeobox code that specifies regions of the developing jaws to assume odontogenic
potential (Sharpe, 1995). Each particular region expresses a unique
combination of homeobox genes which then gives rise to teeth of a particular class. The
molecular basis of this patterning is the differential expression of the coded homeobox nuclear
proteins which regulate downstream gene transcription. The analysis of mice with targeted
mutations in the expression of Msx-1 provide some evidence for this (Satokata and
Maas, 1994). In these mice, the incisors fail to develop and molar development is
arrested at the late bud stage. Mice with targeted mutations in either the Dlx-1 or Dlx-2 genes
have normal tooth development, despite having a number of defects in skeletal elements derived
from proximal first arch mesenchyme. However, targeted null mutations in both Dlx-1 and Dlx-2
results in mice with a phenotype expressing absent maxillary molars (Qiu et al., 1997). Heterologous recombination experiments between mutant and
wild-type maxillary epithelium and mesenchyme indicate that the mutant mesenchyme in these
double homozygous mice has lost its odontogenic potential. The neural crest derived
mesenchyme in the molar region of these mutants appears to have an altered fate, becoming
chondrogenic instead of odontogenic (Thomas et al., 1997).
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Epithelial-mesenchymal Interactions |
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TopIntroductionAn Overview of OdontogenesisPatterning of the DentitionHomeobox GenesEpithelial-mesenchymal...The Role of the...Clinical PerspectivesConclusionsReferences |
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). Recombination experiments have confirmed that prior to the bud stage of
development the potential to induce tooth morphogenesis resides in the epithelium, only
mandibular arch epithelium is capable of inducing the differentiation of a dental papilla in first
arch mesenchyme prior to the bud stage (Mina and Kollar, 1987).
However, the mandibular epithelium can only specify tooth development in mesenchyme that is
neural crest derived, be it cranial or trunk (Lumsden, 1988). After the bud
stage, this inductive potential shifts to the mesenchyme, with odontogenic mesenchyme being
capable of inducing tooth formation when recombined with non-odontogenic epithelium (Kollar and Baird, 1970). The molecular basis for these experimental
observations is dependant upon many of the diffusible protein signalling molecules and growth
factors that are known to mediate reciprocal signalling between cell groups in epithelium and
mesenchyme during development (Table 1). A number of members of
these groups have been identified in the developing tooth germ at various stages of development.
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). Vertebrate Bmp-2 and Bmp-4 are
homologous with the Drosophila decapentaplegic (Dpp) gene which has an
important role in ectodermal-mesodermal signalling in the fly. The expression of Bmp's
has been associated with epithelial-mesenchymal interactions involved in the development of a
number of organs, including the teeth (Vainio et al., 1993; Heikinheimo et al., 1994). Bmp-2, 4, and 7 are all expressed in
the presumptive dental epithelium during early tooth morphogenesis. The expression pattern of
Bmp-4, however, shifts from the epithelium to the condensing dental mesenchyme at the same
time that the inductive potential for odontogenesis shifts from epithelium to mesenchyme. This
suggests that Bmp-4 may be a principle component of the signal responsible for inducing
odontogenic potential in the mesenchyme. Beads expressing Bmp-4 protein are also capable of
inducing the expression of Msx-1, Msx-2 and Bmp-4 in cultured mesenchyme from the tooth
bearing regions (Vainio et al., 1993). Mice which do not express
Msx-1 have molar development that arrests at the late bud stage and mesenchymal expression of
Bmp-4 which is down-regulated. In the presence of Bmp-4 however, these tooth germs are
capable of reaching the cap stage. It is evident that Msx-1 is required to mediate this shift of
Bmp-4 expression from epithelium to mesenchyme, possibly acting as an amplifier of the Bmp-4
signal. Recent in vitro experiments involving the use of noggin (an antagonist of
Bmp-4) have verified the role of epithelial Bmp-4 as providing a positive feedback loop which
maintains the expression of Msx-1 and Bmp-4 in the mesenchyme. This has the effect of
restricting the expression of these genes to the future tooth forming regions (Tucker et al., 1998).
Fibroblast Growth Factors
The fibroblast growth factors (FGFs) are a large family of heparin binding proteins that are
known to mediate the growth and differentiation of cells from a wide variety of developmental
origins (Wilkie et al., 1995). Comprehensive in situ
hybridization studies have shown that Fgf-4, Fgf-8, and Fgf-9 are all expressed in epithelial cells
of the developing tooth germ at times when epithelial-mesenchymal interactions are known to be
regulating odontogenic morphogenesis (Kettunen and Thesleff, 1998).
Expression of Fgf-8 and Fgf-9 is seen initially in the primitive oral epithelium, at the time of
odontogenic initiation this expression becomes restricted to the area of the presumptive dental
epithelium and persists until the beginning of the bud stage. Both Fgf-4 and Fgf-8 expression
then becomes up-regulated later on at the cap stage of development in the enamel knot, and later
again in the secondary enamel knots that form at the sites of future cuspal morphogenesis. These
findings suggest roles for Fgf-8 and Fgf-9 in mediating the initiation of tooth development, and
for Fgf-4 and Fgf-9 in determining coronal morphology.
Sonic Hedgehog
Sonic hedgehog (Shh) is the vertebrate homologue of the Drosophila hedgehog (hh) segment polarity gene which is involved in defining the identity of parasegment borders in
the developing fly embryo. In the vertebrate, Shh encodes a signal peptide that mediates both
long and short range patterning in a number of well known developmental signalling centres (Hammerschmidt et al., 1997). During odontogenesis, Shh is
expressed strongly in the epithelial thickenings of the future tooth forming regions (Bitgood and McMahon, 1995) and also at a later stage of development in the enamel
knot (Vaahtokari et al., 1996a). This expression pattern has led
to speculation that Shh is involved in epithelial signalling both during the initiation of tooth
development and at a later stage during cuspal morphogenesis. Targeted disruption of Shh in
knockout mice results in severe defects of the central nervous system, the axial skeleton, and the
limbs (Chiang et al., 1996). These mice are cyclopic and have
holoprosencephaly, a failure of midline cleavage of the developing forebrain and they die before
birth. As Sonic hedgehog is required for embryonic viability prior to the onset of odontogenesis
in these mutant mice they reveal little regarding its role in tooth development. However, the role
of some downstream target genes in the Shh signalling pathway has recently been investigated in
relation to odontogenesis (Hardcastle et al., 1998). The Gli zinc
finger transcription factors (Gli-1, - 2, - 3) are known to act downstream of Shh. Analysis of mice
with the expression of Gli-2 knocked out revealed abnormal development of the maxillary
incisors, possibly due to a mild form of holoprosencephaly. However, Gli-3 mutants showed
normal development of their dentitions. Double homozygous knockout mice for Gli-2/Gli-3 had
no teeth that developed normally, whereas in double homozygous/heterozygous mutants (Gli-2
- /- , Gli-3 +/- ) maxillary incisor development arrested, and all
molars and the mandibular incisors were microdont. These results have confirmed an essential
role for Shh signalling in odontogenesis and suggest a degree of functional redundancy between
some members of the downstream target genes.
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The Role of the Enamel Knot |
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TopIntroductionAn Overview of OdontogenesisPatterning of the DentitionHomeobox GenesEpithelial-mesenchymal...The Role of the...Clinical PerspectivesConclusionsReferences |
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). In molar teeth, secondary enamel knots also appear at the sites of the future
secondary cusps, almost certainly under the influence of the primary knot. Both the primary and
secondary knot cells express Fgf-4 and are non-dividing; Fgf-4 is known to stimulate
proliferation of both dental epithelium and mesenchyme. It has been proposed that this induced
cell proliferation of the enamel organ in conjunction with the lack of cell division in the enamel
knot allows the growth and folding of the developing cusps (Jernvall et al.,
1994). At the cap stage of development, the cells of the enamel knot undergo
apoptosis and disappear, presumably switching off its signalling function (Vaahtokari
et al., 1996b). The enamel knot is formed during the late bud stage of tooth
development when the capacity to induce tooth morphogenesis is known to reside in the
mesenchyme. The proposed signalling function of the enamel knot implies that an epithelial
derived structure does have a regulatory role to play in the later stages of odontogenesis. The
enamel knot is seemingly necessary for morphogenesis of the tooth germ to progress from the
bud to the cap stage. |
Clinical Perspectives |
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TopIntroductionAn Overview of OdontogenesisPatterning of the DentitionHomeobox GenesEpithelial-mesenchymal...The Role of the...Clinical PerspectivesConclusionsReferences |
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). Family studies have established that incisor and premolar hypodontia is
inherited via an autosomal dominant gene which demonstrates incomplete penetrance (Burzynski and Escobar, 1983). This form of hypodontia, affecting one or
a few teeth (upper lateral incisors and lower second premolars most commonly) has recently been
investigated in relation to the expression of the human MSX-1 and MSX-2 genes (Nieminen et al., 1995). Five Finnish families were studied that included 20
individuals affected with the congenital absence of from one to four teeth, but linkage analysis
excluded these genes as causative loci for this form of hypodontia. However, genetic linkage
analysis in a family affected with a rather more severe form of hypodontia (oligodontia)
involving the absence of all second premolars and third molars has identified a causative locus
on chromosome 4p where the MSX-1 gene resides. Sequence analysis of this region revealed an
Arg31Pro mutation in the homeodomain of the MSX-1 gene in all the affected family members.
It was proposed that this simple mutation prevented the normal integration of the MSX-1
transcription factor with target DNA and other transcription factors. These compromised MSX-1
interactions being critical for the normal development of specific teeth (Vastardis et al., 1996).
Many of the genes that are known to be key players in odontogenesis also have widespread roles
during development of the craniofacial complex. Mutations in some of these genes have now
been identified in a number of human craniofacial anomalies. A locus for one rare autosomal
dominant form of craniosynostosis (Boston type) has been mapped to chromosome 5qter. The
human MSX-2 gene is localized here and affected individuals from one family had a simple
Hist7Pro mutation in the MSX-2 homeodomain (Jabs et al., 1993). No mutations were found in the MSX-2 gene of individuals affected with the more
common Crouzon or Apert craniosynostotic syndromes. However, analysis of the function of
MSX-2 in the development of the Boston form of this disease may well help in our
understanding of these more common forms. The tricho-dento-osseous syndrome (TDO) is an
autosomal dominant disorder characterized by abnormal hair, enamel hypoplasia and
taurodontism, and cranial thickening associated with the frontal/mastoid air sinuses. The TDO
locus has been mapped to chromosome 17q21, a region that includes the human DLX-3 and
DLX-7 genes. A 4-basepair deletion in DLX-3 has very recently been identified which correlated
with the TDO phenotype in six families. This mutation produced a frameshift and premature
termination codon in the transcribed DLX-3 transcription factor (Price et al.,
1998).
The human SHH gene has been identified as the HPE3 gene on chromosome
7q36, the first known gene to cause holoprosencephaly. Five affected families have recently been
identified that carry mutations in the SHH gene. Two of these mutations truncate the
gene, whereas the others replace critical residues in the transcribed SHH protein (Roessler et al., 1996). This study confirms that alterations in SHH
can lead to dominant effects on human development. Patched (Ptc) is a putative
12-transmembrane domain protein that acts as a receptor for the Shh ligand (Stone et al., 1996). Patched is an unusual receptor in that it represses the Shh
signal unless bound by the ligand. Mutation of the human Patched (PTCH) gene occurs
in the autosomal dominant basal cell naevus (Gorlins) syndrome (Hahn et al.,
1996; Johnson et al., 1996). This syndrome is
characterized by multiple basal cell carcinomas of the skin, medulloblastomas, and multiple
keratocysts of the jaws. These patients can also develop anomalies found in holoprosencephaly
including skeletal abnormalities and cleft lip/palate. As a suppressor of Shh it would seem that a
loss of function PTCH mutation can cause abnormal growth in certain cell types (Dean, 1996).
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Conclusions |
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TopIntroductionAn Overview of OdontogenesisPatterning of the DentitionHomeobox GenesEpithelial-mesenchymal...The Role of the...Clinical PerspectivesConclusionsReferences |
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Acknowledgments |
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Notes |
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References |
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TopIntroductionAn Overview of OdontogenesisPatterning of the DentitionHomeobox GenesEpithelial-mesenchymal...The Role of the...Clinical PerspectivesConclusionsReferences |
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