The Questions of Developmental Biology

Soon afterward, the expression pattern of BMP4 and FGF8 changes, and the sites of the
tooth primordia are determined by the interactions between these same molecules in the
epithelium. FGF8 induces Pax9 expression in the underlying ectomesenchyme, while BMP4
inhibits Pax9 expression. Pax9 is a transcription factor whose expression in the ectomesenchyme
is critical for the initiation of tooth morphogenesis, and in Pax9-deficient mice, tooth
development ceases early. The only places where ectomesenchyme condense and teeth develop
are where FGF8 is present and BMPs are absent (Vainio et al. 1993; Neubüser et al. 1997). Thus,
spaces develop between the teeth.
At this time, the epithelium possesses the potential to generate tooth structures out of
several types of mesenchyme cells (Mina and Kollar 1987; Lumsden 1988b). However, this
tooth-forming potential soon becomes transferred to the ectomesenchyme that has aggregated
beneath it. These ectomesenchymal cells form the dental papilla and are now able to induce
tooth morphogenesis in other epithelia (Kollar and Baird 1970). At this stage, the jaw epithelium
has lost its ability to instruct tooth formation in other mesenchymes. Thus, the "odontogenic
potential" has shifted from the epithelium to the mesenchyme. This shift in the odontogenic
potential coincides with a shift in the synthesis of BMP4 from the epithelium to the
ectomesenchyme.
As the dental mesenchyme cells condense, they are induced to synthesize the membrane
protein syndecan and the extracellular matrix protein tenascin. These proteins (which can bind
each other) appear at the time the epithelium induces mesenchymal aggregation, and Thesleff and
her colleagues (1990) have proposed that these two molecules may interact to bring about this
condensation. Moreover, after the ectomesenchyme has aggregated, it begins to secrete BMP4 as
well as other growth and differentiation factors (FGF3, BMP3, HGF, and activin) (Wilkinson et
al. 1989; Thesleff and Sahlberg 1996). These proteins from the ectomesenchyme induce a critical
structure in the epithelium. This structure is called the enamel knot, and it functions as the major
signaling center for tooth development (Jernvall et al. 1994). This group of cells appears as a
nondividing population of cells in the center of the growing cusps. Moreover, in situ
hybridization has demonstrated that the enamel knot is the source of Sonic hedgehog, FGF4,
BMP7, BMP4, and BMP2 secretion (Figure 13.9B; Koyama et al. 1996; Vaahtokari et al. 1996a).
As a nondividing population secreting growth factors capable of being received by both the
epithelium and the ectomesenchyme, the enamel knot is thought to direct the cusp morphogenesis
of the tooth and to be critical in directing the evolutionary changes of tooth structure in mammals
(Jernvall 1995).
The mesenchyme cells begin to differentiate into odontoblasts, and tenascin expression is
induced at much higher levels and at the same sites as alkaline phosphatase expression. Both of
these proteins have been associated with bone and cartilage differentiation, and they may promote
the mineralization of the extracellular matrix (Mackie et al. 1987). Finally, as the odontoblast
phenotype emerges, osteonectin and type I collagen are secreted as components of the
extracellular matrix. The enamel knot disappears through apoptosis, responding to its own BMP4
(Vaahtokari et al. 1996b; Jernvall et al. 1998). By this steplike process, the cranial neural crest
cells of the jaw are transformed into the dentin-secreting odontoblasts.
Neuronal Specification and Axonal Specificity
Not only do neuronal precursor cells and neural crest cells migrate to their place of
function, but so do the axons extending from the cell bodies of neurons. Unlike most cells, whose
parts all stay in the same place, the neuron is able to produce axons that may extend for meters.