Tooth Induction

Abstract

Tooth development is a sequential process governed by reciprocal interactions between ectoderm and neural crest‐derived mesenchyme. Initially, the inductive signal resides in the epithelium, but during subsequent developmental stages, it shifts to the mesenchyme. The complex signalling and cellular cross‐talk generate differentiated cell lineages which will ultimately form the intricate tooth structure, composed of heterogeneous cellular compartments and mineralised matrices, namely enamel, dentin and cementum. The first morphological sign of tooth development is dental lamina, a thickening of the oral epithelium at the sites of future tooth rows. Humans generate two separate dentitions: primary and permanent teeth which are formed from primary dental lamina and its extension (successional dental lamina), respectively. Many signalling pathways involved in tooth development have been identified and characterised. While some molecules demonstrate transient expression during tooth morphogenesis, many signalling pathways are active at all stages of tooth development and regulate tooth induction, morphogenesis and cytodifferentiation.

Key Concepts

  • Tooth development is regulated by a chain of epithelial–mesenchymal interactions that generate unique morphological features which mark different stages of development.
  • The first sign of tooth formation is an epithelial thickening known as the dental lamina. In humans, the initial dental lamina generates primary dentition and extends into a structure called successional lamina from which permanent teeth develop.
  • Budding morphogenesis and crown formation are regulated by signals emanating from the epithelial signalling centres called initiation knots and enamel knots, respectively.
  • Many signalling molecules and receptors are expressed at different stages of tooth development and have been shown to play important roles in the regulation of tooth morphogenesis and in induction of the differentiation of odontoblasts and ameloblasts.
  • Morphogenesis of the replacement and successionally formed teeth is similar to the morphogenesis of the primary teeth and is regulated by the same signalling pathways.

Keywords: tooth; development; induction; signal; dental lamina; initiation knot; enamel knot; stem cells; crown; root

Figure 1. Schematic presentation of the morphology of tooth development. (a) Dental lamina, a thickening of the epithelium in the upper and lower jaw, marks the initiation of teeth. (b) Individual tooth development is marked by the formation of dental placodes within the dental lamina. (c) The budding of the epithelium is driven by the Initiation Knot (IK in (a)) and accompanied by condensation of the neural crest‐derived mesenchymal cells. (d) The primary enamel knot (1°EK) appears in the epithelium as it undergoes folding morphogenesis and develops into the cap stage. Extension of the dental lamina (asterisk) marks the initiation of the secondary, replacement tooth lingually from the primary tooth. (e) The form of the tooth crown is established during the bell stage, and secondary enamel knots appear in the tips of future cusps. (f) Differentiation of the odontoblasts and ameloblasts and deposition of dentin and enamel start in the cusp tips. (g) After completion of crown formation, dentinogenesis continues in the forming roots and the tooth erupts into the oral cavity.
Figure 2. Schematic representation of signalling networks regulating the initial stages of tooth morphogenesis. The signalling tissues and genes specifically expressed in those tissues are marked in black letters, while red letters indicate signalling molecules that regulate the expression of specific transcription factors. Red arrows indicate active signalling, while grey arrows indicate continuing tooth morphogenesis.
Figure 3. Visualisation of enamel knots, signalling centres in the epithelium. (a) Transverse section of a cap stage mouse tooth (embryonic day 14). Cells of the enamel knot stop proliferating as shown by the lack of bromodeoxyuridine (BrdU) incorporation (red). (b) Three‐dimensional view of the enamel knot of the cap stage tooth as visualised by the lack of BrdU incorporation (red) and the expression of Fgf4 (blue). (c) Transverse section of a cap stage mouse tooth (embryonic day 14). Fgf‐4 expression, as visualised by in situ hybridisation (blue), is limited to the enamel knot. (d) Sagittal section of an embryonic day 16 mouse mandible. Fgf4 expression in the secondary enamel knots (sk) of the first molar (m1) at the bell stage and in the primary enamel knot (pk) of the second molar (m2) at the cap stage. de, dental epithelium; dm, dental mesenchyme. Bars, 100 µm. Courtesy of Jukka Jernvall and Päivi Kettunen.
Figure 4. Schematic of root formation. (a) Completion of crown formation and initiation of root formation coincides with disappearance of stem cells (SC) located between the inner (IEE) and outer (OEE) enamel epitheliums of the cervical loop. (b) In the developing root, cervical loops are replaced by a bilayer of IEE and OEE that fragments and forms Hertwig's epithelial root sheet (HERS). Cementum is deposited by cementoblasts differentiating from the dental follicle after the epithelial root sheath disrupts. The periodontal ligament forms and the development of alveolar bone continues.
close

References

Aberg T, Wang XP, Kim JH, et al. (2004) Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Developmental Biology 270 (1): 76–93.

Ahtiainen L, Uski I, Thesleff I and Mikkola ML (2016) Early epithelial signaling center governs tooth budding morphogenesis. Journal of Cell Biology 214 (6): 753–767.

Bei M (2009a) Molecular genetics of tooth development. Current Opinion in Genetics & Development 19 (5): 504–510.

Feng J, Mantesso A, De Bari C, Nishiyama A and Sharpe PT (2011) Dual origin of mesenchymal stem cells contributing to organ growth and repair. Proceedings of the National Academy of Sciences of the United States of America 108 (16): 6503–6508.

Harada H, Kettunen P, Jung HS, et al. (1999) Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling. Journal of Cell Biology 147 (1): 105–120.

Huang X, Xu X, Bringas P Jr, Hung YP and Chai Y (2010) Smad4‐Shh‐Nfic signaling cascade‐mediated epithelial‐mesenchymal interaction is crucial in regulating tooth root development. Journal of Bone and Mineral Research 25 (5): 1167–1178.

Huggins CB, McCarroll HR and Dahlberg AA (1934) Transplantation of tooth germ elements and the experimental heterotopic formation of dentin and enamel. Journal of Experimental Medicine 60 (2): 199–210.

Jarvinen E, Salazar‐Ciudad I, Birchmeier W, et al. (2006) Continuous tooth generation in mouse is induced by activated epithelial Wnt/beta‐catenin signaling. Proceedings of the National Academy of Sciences of the United States of America 103 (49): 18627–18632.

Jernvall J and Thesleff I (2000) Reiterative signaling and patterning during mammalian tooth morphogenesis. Mechanisms of Development 92 (1): 19–29.

Jia S, Zhou J, Gao Y, et al. (2013) Roles of Bmp4 during tooth morphogenesis and sequential tooth formation. Development 140 (2): 423–432.

Jia S, Kwon HE, Lan Y, et al. (2016) Bmp4‐Msx1 signaling and Osr2 control tooth organogenesis through antagonistic regulation of secreted Wnt antagonists. Developmental Biology 420 (1): 110–119.

Jussila M, Aalto AJ, Sanz Navarro M, et al. (2015) Suppression of epithelial differentiation by Foxi3 is essential for molar crown patterning. Development 142 (22): 3954–3963.

Juuri E, Saito K, Ahtiainen L, et al. (2012) Sox2+ stem cells contribute to all epithelial lineages of the tooth via Sfrp5+ progenitors. Developmental Cell 23 (2): 317–328.

Kaukua N, Shahidi MK, Konstantinidou C, et al. (2014) Glial origin of mesenchymal stem cells in a tooth model system. Nature 513 (7519): 551–554.

Kollar EJ and Baird GR (1970) Tissue interactions in embryonic mouse tooth germs. II. The inductive role of the dental papilla. Journal of Embryology and Experimental Morphology 24 (1): 173–186.

Kratochwil K, Galceran J, Tontsch S, Roth W and Grosschedl R (2002) FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(−/−) mice. Genes and Development 16 (24): 3173–3185.

Laurikkala J, Kassai Y, Pakkasjarvi L, Thesleff I and Itoh N (2003) Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot. Developmental Biology 264 (1): 91–105.

Laurikkala J, Mikkola ML, James M, et al. (2006) p63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation. Development 133 (8): 1553–1563.

Li J, Huang X, Xu X, et al. (2011) SMAD4‐mediated WNT signaling controls the fate of cranial neural crest cells during tooth morphogenesis. Development 138 (10): 1977–1989.

Li J, Feng J, Liu Y, et al. (2015) BMP‐SHH signaling network controls epithelial stem cell fate via regulation of its niche in the developing tooth. Developmental Cell 33 (2): 125–135.

Liu F, Chu EY, Watt B, et al. (2008) Wnt/beta‐catenin signaling directs multiple stages of tooth morphogenesis. Developmental Biology 313 (1): 210–224.

Lumsden AG (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.

Mina M and Kollar EJ (1987) The induction of odontogenesis in non‐dental mesenchyme combined with early murine mandibular arch epithelium. Archives of Oral Biology 32 (2): 123–127.

Mustonen T, Ilmonen M, Pummila M, et al. (2004) Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages. Development 131 (20): 4907–4919.

O'Connell DJ, Ho JW, Mammoto T, et al. (2012) A Wnt‐bmp feedback circuit controls intertissue signaling dynamics in tooth organogenesis. Science Signaling 5 (206): ra4.

Ogawa T, Kapadia H, Feng JQ, et al. (2006) Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development. Journal of Biological Chemistry 281 (27): 18363–18369.

Ohazama A, Modino SA, Miletich I and Sharpe PT (2004) Stem‐cell‐based tissue engineering of murine teeth. Journal of Dental Research 83 (7): 518–522.

Oshima M, Mizuno M, Imamura A, et al. (2011) Functional Tooth Regeneration Using a Bioengineered Tooth Unit as a Mature Organ Replacement Regenerative Therapy. Plos One 6 (7): e21531.

Saadi I, Das P, Zhao M, et al. (2013) Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud‐to‐cap stage transition in tooth development. Development 140 (13): 2697–2702.

Salazar‐Ciudad I and Jernvall J (2010) A computational model of teeth and the developmental origins of morphological variation. Nature 464 (7288): 583–586.

Vainio S, Karavanova I, Jowett A and Thesleff I (1993) Identification of BMP‐4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development. Cell 75 (1): 45–58.

Wang XP, Suomalainen M, Jorgez CJ, et al. (2004) Follistatin regulates enamel patterning in mouse incisors by asymmetrically inhibiting BMP signaling and ameloblast differentiation. Developmental Cell 7 (5): 719–730.

Wang XP, O'Connell DJ, Lund JJ, et al. (2009) Apc inhibition of Wnt signaling regulates supernumerary tooth formation during embryogenesis and throughout adulthood. Development 136 (11): 1939–1949.

Wang Y, Li L, Zheng Y, et al. (2012) BMP activity is required for tooth development from the lamina to bud stage. Journal of Dental Research 91 (7): 690–695.

Vidovic I, Banerjee A, Fatahi R, et al. (2017) alphaSMA‐Expressing Perivascular Cells Represent Dental Pulp Progenitors In Vivo. Journal of Dental Research 96 (3): 323–330.

Yokohama‐Tamaki T, Ohshima H, Fujiwara N, et al. (2006) Cessation of Fgf10 signaling, resulting in a defective dental epithelial stem cell compartment, leads to the transition from crown to root formation. Development 133 (7): 1359–1366.

Zhang Z, Lan Y, Chai Y and Jiang R (2009) Antagonistic actions of Msx1 and Osr2 pattern mammalian teeth into a single row. Science 323 (5918): 1232–1234.

Zhao H, Feng J, Seidel K, et al. (2014) Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell 14 (2): 160–173.

Further Reading

Balic A and Thesleff I (2015) Tissue Interactions Regulating Tooth Development and Renewal. Current Topics in Developmental Biology 115: 157–158.

Bei M (2009b) Molecular genetics of tooth development. Current Opinion in Genetics & Development 19 (5): 504–510.

Huang XF and Chai Y (2012) Molecular regulatory mechanism of tooth root development. International Journal of Oral Science 4 (4): 177–181.

Jernvall J and Thesleff I (2012) Tooth shape formation and tooth renewal: evolving with the same signals. Development 139 (3487–97): 2012.

Kangas AT, Evans AR, Thesleff I and Jernvall J (2004) Non‐independence of mammalian dental characters. Nature 432: 211–214.

Lammi L, Arte S, Somer M, et al. (2004) Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. American Journal of Human Genetics 74: 1043–1050.

Li C‐Y, Prochazka J, Goodwin AF and Klein OD (2014) Fibroblast growth factor signaling in mammalian tooth development. Odontology 102: 1–13.

Mikkola ML (2009) Molecular aspects of hypohidrotic ectodermal dysplasia. American Journal of Medical Genetics. Part A 149A (9): 2031–2036.

Nanci A (2013) Ten Cate's Oral Histology: Development, Structure and Function. St Louis, MO: Mosby.

Ruch JV, Lesot H and Begue‐Kirn C (1995) Odontoblast differentiation. International Journal of Developmental Biology 39: 51–68.

Whitlock JA and Richman JM (2013) Biology of tooth replacement in amniotes. International Journal of Oral Science 5 (2): 66–70.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Balic, Anamaria(Jul 2017) Tooth Induction. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001143.pub3]