|
HOME :: CHAPTER 13 :: TOOTH FORMATION IN MAMMALS :: TOOTH DEVELOPMENT |
Tooth Development
During the morphogenesis of any organ, numerous dialogues occur between interacting tissues. In epithelial-mesenchymal interactions, the mesenchyme influences the epithelium; the epithelial tissue, once changed by the mesenchyme, can secrete factors that change the mesenchyme. Such interactions continue until an organ is formed with organ-specific mesenchyme cells and organ-specific epithelia. Some of the most extensively studied interactions are those that form the mammalian tooth. Here, the neural crest-derived mesenchyme cells become the dentin-secreting odontoblasts, while the jaw epithelium differentiates into the enamel-secreting ameloblasts. This can be seen using the transgenic mouse mentioned earlier, wherein cranial neural crest cells are stained blue (Figure 1; Chai et al. 2000).
|
| Figure 1 Changes in the cranial neural crest cell population as teeth are formed. Originally, the neural crest ectomesenchyme induces and maintains an ectodermal placode. The placode grows and causes the mesenchyme cells to condense beneath it. The mesenchyme cells push into the ectodermal bulge to create the dental papilla. These cells become the odontoblasts of the teeth and become part of the dentin-forming pulp. The figures below show neural crest cells stained blue; the ectodem has been counterstained pink. (After Thesleff and Sahlberg 1996; photographs from Chai et al. 2000, courtesy of Y. Chai.) (Click image to enlarge.) |
Tooth development begins when the mandibular (jaw) epithelium causes neural crest-derived ectomesenchyme (i.e., mesenchyme produced from the ectoderm) to aggregate at specific sites. The polarity of the mandibular epithelium is determined by interactions between Bmp4, which is located distally, and Fgf8, which is located proximally (closest to the skull). Those teeth formed in the Fgf8 regions will become molars, while those teeth that develop in the Bmp4 regions will become incisors (Tucker et al. 1998). 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 1988). 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 2; 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).
|
| Figure 2 Concentrations of four paracrine factors in the region where morphogenesis and differentiation are occurring in the 14-day embryonic mouse lower molar. The boundary of the tooth epithelium is shown in white in the lower photos. The paracrine factors are secreted by the enamel knot, a mass of nondividing epithelial cells. (The concentration of BrdU shows that the cells of the enamel knot are not replicating DNA.) Above each in situ hybridization photograph is a serial reconstruction of the area of gene expression. (From Jernvall 1995; photographs courtesy of A. Vaahtokari, J. Jernvall, and I. Thesleff.) (Click image to enlarge.) |
Why all these factors secreted from the enamel knot? It seems that they have several overlapping and unique functions. FGF4 and SHH are both found to regulate the proliferation of cells around the enamel knot. FGF4 stimulates mitosis in both the epithelial cells and the mesenchyme cells, and it induces mesenchymal Fgf3, which is critical in epithelial morphogenesis from the bud to the cap stage. SHH also affects mesenchymal and epithelial tissues and it is required for epithelial growth. BMPs from the mesenchyme are critical in the formation of the enamel knots, and the BMPs (and FGFs) made from the enamel knots are required for the continued mesenchymal growth. Moreover, BMP from the enamel knot can induce its own inhibitor, ectodin, which diffuses throughout the entire tooth bud. However, FGFs and SHH counteract ectodin, thereby allowing BMPs to work in the limited area around the enamel knot (Laurikkala et al. 2003).
As the dental mesenchyme cells begin to differentiate into odontoblasts, they begin to secrete several molecules that promote mineralization of the extracellular matrix. These proteins include tenascin, bono-1, dental sialophosphoprotein, and alkaline phosphatase (Mackie et al. 1987; James et al. 2004). 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.
Why don’t humans have more than two sets of teeth?
Many humans in today’s industrialized nations live almost 80 years—twice the life span generally associated with our species throughout history. An Englishman born during the Revolutionary War could expect to live 35 years. Only rare individuals, like George Washington, lived long enough to need false teeth. Our teeth have not adapted to this new longevity. Without frequent brushing and dental care, their warranty runs out after the first 40 years. But other animals have teeth that keep growing, or have the ability to replace their teeth several times. What do they have that we don’t?
The answer appears to be tooth epithelial stem cells. Humans have only two sets of teeth in their lifetime, and once the second set is formed, these teeth stop growing. Mouse and rabbit incisors, however, grow continuously throughout their lives. (This is why these animals need to gnaw. If they do not grind their front teeth, they continue to grow and can prevent the animal from eating.) Thus, these incisors have stem cells for both the mesenchyme and epithelial components. The epithelial stem cell of mouse incisors appears to be located in the apical end of the tooth (away from the crown, in a region known as the stellate reticulum). In mouse molars and in all human teeth, this area is lost after crown formation, and the ameloblast precursor cells that remain form the root of the tooth (Harada et al. 1999; Tummers and Thesleff 2003).
Non-mammalian vertebrates can form teeth over and over again (think of the multiple rows of teeth in a shark jaw, for instance). Huysseune and Thesleff (2004) have presented evidence that these animals are able to do this because the epithelium at the base of their tooth buds forms a bulge containing epithelial stem cells. Indeed, the process by which these animals replace teeth would be very similar to the mechanisms by which we replace hair.
Literature Cited
Chai, Y. and 8 others. 2000. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 127: 1671–1679.
Harada, H., P. Kettunen, H. S. Jung, T. Mustonen, Y. A. Wang, and I. Thesleff. 1999. Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling. J. Cell Biol. 147: 105–120.
Huysseune, A. and I. Thesleff. 2004. Continuous tooth replacment: Possible involvement of epithelial stem cells. BioEssays 26: 665–671.
James, M. J., E. Järvinen, and I. Thesleff. 2004. Bono1: A gene associated with regions of deposition of bone and dentine. Gene Expr. Pattern 4: 595–599.
Jernvall, J. 1995. Mammalian molar cusp patterns: Developmental mechanisms of diversity. Acta Zool. Fennica 198: 1–61.
Jernvall, J., P. Kettunen, I. Karavanova, L. B. Martin and I. Theseleff. 1994. Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: Non-dividing cells express growth stimulating Fgf-4 gene. Int. J. Dev. Biol. 38: 463–469.
Jernvall, J., T. Aberg, P. Kettunen, S. Keränen and I. Thesleff. 1998. The life history of an embryonic signaling center: BMP4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. Development 125: 161–169.
Koyama, E. and 10 others. 1996. Polarizing activity, Sonic hedgehog, and tooth development in embryonic and postnatal mouse. Dev. Dynam. 206: 59–72.
Laurikkal, J., Y. Kassai, L. Pakkasjärvi, I.Thesleff, and N. Itoh. 2003. Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot. Dev. Biol. 264: 91–105.
Lumsden, A. G. S. 1988. Spatial organization of the epithelium and the role of neural crest cells in the initiation of the mammalian tooth germ. Development 103 [Suppl.]: 155–169.
Mackie, E. J., I. Thesleff and R. Chiquet-Ehrismann. 1987. Tenascin is associated with chondrogenic and osteogenic differentiation in vivo and promotes chondrogenesis in vivo. J. Cell Biol. 105: 2569–2579.
Mina, M. and E. J. Kollar. 1987. The induction of odontogenesis in non-dental mesenchyme combined with early murine mandibular arch epithelium. Arch. Oral Biol. 32: 123–127.
Neubüser, A., H. Peters, R. Ballig and G. R. Martin. 1997. Antagonistic interactions between FGF and BMP signaling pathways: A mechanism for positioning the sites of tooth formation. Cell 90: 247–255.
Thesleff, I. and C. Sahlberg. 1996. Growth factors as inductive signals regulating tooth morphogenesis. Semin. Cell Dev. Biol. 7: 185–193.
Thesleff, I., A. Vaahtokari and S. Vainio. 1990. Molecular changes during determination and differentiation of the dental mesenchyme cell lineage. J. Biol. Bucalle 18: 179–188.
Tucker, A. S., K. L. Matthews and P. T. Sharpe. 1998. Transformation of tooth type induced by inhibition of BMP signaling. Science 282: 1136–1138.
Tucker, A. and P. Sharpe. 2004. The cutting-edge of mammalian development: how the embryo makes teeth. Nature Rev. Genet. 5: 499–508.
Tummers, M and I. Thesleff. 2003. Root or crown: a developmental choice orchestrated by the differential regulation of the epithelial stem cell niche in the tooth of two rodent species. Development 130: 1049–1057.
Vaahtokari, A., T. Aberg, J. Jernvall, S. Keränen and I. Thesleff. 1996a. The enamel knot as a signalling center in the developing mouse tooth. Mech. Dev. 54: 39–43.
Vaahtokari, A., T. Aberg and I. Thesleff. 1996b. Apoptosis in the developing tooth: Association with an embryonic signaling center and suppression by EGF and FGF-4. Development 122: 121–129.
Vainio, S., I. Karavanova, A. Jowett and I. Thesleff. 1993. Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development. Cell 75: 45–58.
Wilkinson, D. G., S. Bhatt and A. P. McMahon. 1989. Expression of the FGF-related proto-oncogene int-2 suggests multiple roles in fetal development. Development 105: 131–136.
© All the material on this website is protected by copyright. It may not be reproduced in any form without permission from the copyright holder.
|
HOME :: CHAPTER 13 :: TOOTH FORMATION IN MAMMALS :: TOOTH DEVELOPMENT |