By
fajara
*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-Hoxhomeobox and
other transcriptional regulators
* 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
*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 β-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 Shhepithelial 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).
* The important role that Msx genes play in tooth
development is exemplified by mice lacking Msx gene
function. Msxldeficient mice exhibit an arrest in tooth
development at the bud stage, while Msx2-deficient mice
exhibit late defects in tooth development. The coexpression of Msx, Bmp, Lef1, and Activin βA genes and the
coincidence of tooth phenotypes in the various knockout
mice suggest that these genes reside within a common
genetic pathway. Results summarized here indicate
that Msx1 is required for the transmission
of Bmp4 expression from dental epithelium to mesenchyme
and also for Lef1 expression. In addition, we consider the
role of other signaling molecules in the epithelialmesenchymal interactions leading to tooth formation, the
role that transcription factors such as Msx play in the
propagation of inductive signals, and the role of
extracellular matrix. Last, as a unifying mechanism to
explain the disparate tooth phenotypes in Msxl- and Msx2deficient mice, we propose that later steps in tooth
morphogenesis molecularly resemble those in early tooth
development.