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Downloaded from http://cshperspectives.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling Networks Regulating Tooth Organogenesis and Regeneration, and the Specification of Dental Mesenchymal and Epithelial Cell Lineages Maria Jussila and Irma Thesleff Developmental Biology Program Institute of Biotechnology, Biokeskus 1, P.O. Box 56, University of Helsinki, Helsinki FIN-00014, Finland Correspondence: maria.jussila@helsinki.fi SUMMARY Teeth develop as ectodermal appendages from epithelial and mesenchymal tissues. Tooth organogenesis is regulated by an intricate network of cell–cell signaling during all steps of development. The dental hard tissues, dentin, enamel, and cementum, are formed by unique cell types whose differentiation is intimately linked with morphogenesis. During evolution the capacity for tooth replacement has been reduced in mammals, whereas teeth have acquired more complex shapes. Mammalian teeth contain stem cells but they may not provide a source for bioengineering of human teeth. Therefore it is likely that nondental cells will have to be reprogrammed for the purpose of clinical tooth regeneration. Obviously this will require understanding of the mechanisms of normal development. The signaling networks mediating the epithelial-mesenchymal interactions during morphogenesis are well characterized but the molecular signatures of the odontogenic tissues remain to be uncovered. Outline 1 Morphogenesis and cell 4 Regulation of tooth replacement, continuous differentiation during tooth development growth, and stem cells in teeth 2 Signal networks and signaling centers 5 Future challenges: stem cell-based bioengineering of teeth 3 Regulation of the identity and 6 Concluding remarks differentiation of odontogenic mesenchymal and epithelial cell lineages References Editors: Patrick P.L. Tam, W. James Nelson, and Janet Rossant Additional Perspectives on Mammalian Development available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a008425 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a008425 1 Downloaded from http://cshperspectives.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press M. Jussila and I. Thesleff Teethare one of the most diverse organs in vertebrates both simpler in shape. Thus, during evolution the complexity morphologically and functionally. Mammalian teeth be- of tooth shape has increased, whereas the replacement ca- long to four tooth families: incisors, canine, premolars, pacity has been reduced. and molars, and they are replaced either once or not at The same conserved signaling pathways that regulate all. Humans have teeth from all four tooth families and ex- most aspects of embryonic development are required for cluding molars, the teeth are replaced once (Fig. 1A). The tooth development, and the core regulatory network seems laboratory mouse (Mus musculus), which is the most com- to have been in place already when teeth appeared in evolu- mon model animal in tooth development studies, has a tion (Fraser et al. 2009; Tummers and Thesleff 2009). It is much derived dentition. It lacks the canine and premolars noteworthy that teeth develop as epithelial appendages and has only one incisor and three molars separated by a and share the same regulatory molecules during the first toothless diastema in each half of the jaw (Fig. 1B). Further- steps of initiation and morphogenesis with other ectoder- more, the mouse incisors grow continuously but the teeth mal organs. However, unlike many other human epithelial are not replaced. In contrast, reptiles, fish, and amphibians appendages, human teeth have no regenerative capacity. can replace their teeth multiple times during the life of the The adult human teeth contain stem cells that are capable animal. Teeth of these nonmammalian species are usually of differentiating to cells producing the extracellular matrix AB Incisors Incisors Canine Premolars Diastema Molars Molars C Dental lamina Placode Bud Cap Bell Eruption Epithelium Placode Enamel knot Secondary Enamel Stellate enamel knot Dentin reticulum ri Juu E. E E. Dental Ameloblasts Developing Dental pulp Mesen- Mesen- mesen- Dental permanent chyme chyme chyme papilla Odontoblasts tooth Alveolar bone Cell Initiation Morphogenesis differentiation Matrix secretion Figure 1. The dental formula of human and mouse, and a schematic representation of tooth development. The per- manent dentition of human consists of two incisors, a canine, two premolars, and three molars in each half of the jaw (A). Mice have one incisor and three molars separated by a toothless diastema in each half of the jaw (B). Tooth de- velopment starts from the dental lamina, a thickening of the epithelium. Individual placodes form within the dental lamina. The growing epithelium forms a bud and the dental mesenchyme condenses around the epithelium. During morphogenesis, the epithelial tissue folds to cap and bell shapes. Primary and secondary enamel knots in the enamel organ regulate the growth and shape of the tooth. During cell differentiation, enamel-secreting ameloblasts and dentin-secreting odontoblasts mature from the epithelial and mesenchymal cell compartments. The permanent tooth develops lingually to the deciduous tooth from an extension of the dental lamina (C). 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a008425 Downloaded from http://cshperspectives.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling Networks Regulating Tooth Development of tooth-specific mineralized tissues, but so far they have enamel epithelium during the bell stage determine the not been shown to have morphogenetic potential. The re- size and shape of the tooth crown. The shape becomes fixed placement of adult teeth in humans by tissue engineering when the organic matrices of dentin and enamel mineralize appears still a distant goal and it is obvious that more because no remodeling of either dentin or enamel takes research on stem cell regulation and the molecular control place later. of early tooth development is required. In this article we Root formation is initiated after crown development review the current knowledge about the mechanisms in- when ameloblast differentiation reaches the future crown- volved in tooth morphogenesis and replacement, and how root boundary, and the cells of the inner enamel epithelium the epithelial and mesenchymal cell lineages acquire odon- no longer differentiate into ameloblasts. Instead they form togenic competence and differentiate into tooth-specific the Hertwig’s epithelial root sheath (HERS) with the outer cells depositing the dental hard tissues, and discuss the fu- enamel epithelium. HERS proliferates and migrates down- ture challenges and scenarios of tooth bioengineering. ward guiding root formation, and it also induces the differ- entiation of odontoblasts forming root dentin. HERS has a limited growth potential, which determines the length of 1 MORPHOGENESIS AND CELL the root. The disintegration of HERS results in the forma- DIFFERENTIATION DURING TOOTH tion of an epithelial network called epithelial rests of Malas- DEVELOPMENT sez (ERM) and this allows the cells of dental follicle to come Teethare initiated from two tissue components: the surface in contact with root dentin and their differentiation into epithelium and the underlying mesenchyme. The dental cementoblasts depositing cementum on the root surface. mesenchyme derives from cranial neural crest cells that The periodontal ligament that connects the tooth to the migrate into the frontonasal process and first branchial bone is formed by fibroblasts differentiating from the den- arch.Inmammalstheepitheliumoriginatesfromectoderm, tal follicle cells. In addition, the dental follicle gives rise to whereas in fish and some amphibians, pharyngeal teeth de- osteoblasts that form the alveolar bone where the fibers of rive from the endoderm. the periodontal ligament are embedded (Nanci 2008). The first sign of tooth development is the formation The dental follicle has an important function later in tooth of the dental lamina, a horseshoe-shaped epithelial stripe eruption as it regulates bone remodeling around the tooth along the mandible and maxilla (Fig. 3B). The teeth form (Marks and Cahill 1987). within the dental lamina, where their development starts from placodes, local thickenings of the epithelium (Figs. 2 SIGNAL NETWORKS AND SIGNALING CENTERS 1C and 3B,C). Probably all teeth in one tooth family are in- itiated sequentially from a single placode. For instance, the All aspects of tooth morphogenesis are regulated by mouse molars develop successionally, starting from the first epithelial-mesenchymal interactions, which are mediated molar and followed by initiation of the second and third by the conserved signaling pathways including Hedgehog molars from a posterior extension of the dental epithelium. (Hh), Wnt, Fibroblast growth factor (FGF), Transforming The individual teeth develop from an epithelial bud growth factor b (Tgfb), Bone morphogenic protein (Bmp), that grows down to the underlying mesenchyme. The neu- and Ectodysplasin (Eda) (Fig. 2). Their interactions, targets, ral crest-derived mesenchyme becomes specified asthe den- and expression patterns have been elucidated in considerable tal mesenchyme condenses around the bud and gives rise to detail in teeth (http://bite-it.helsinki.fi; Bei 2009b; Tum- all the dental tissues except enamel.

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