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Molecular and Cellular Mechanisms of Tooth Development, Homeostasis and Repair Tingsheng Yu1 and Ophir D

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Molecular and Cellular Mechanisms of Tooth Development, Homeostasis and Repair Tingsheng Yu1 and Ophir D © 2020. Published by The Company of Biologists Ltd | Development (2020) 147, dev184754. doi:10.1242/dev.184754 REVIEW Molecular and cellular mechanisms of tooth development, homeostasis and repair Tingsheng Yu1 and Ophir D. Klein1,2,* ABSTRACT ever-growing, teeth, are highly specialized and erupt continuously ’ The tooth provides an excellent system for deciphering the molecular throughout the animal s life, with a large percentage of their crowns mechanisms of organogenesis, and has thus been of longstanding remaining buried inside the jaw bones. Moreover, hypselodont interest to developmental and stem cell biologists studying embryonic teeth, such as the incisors of lagomorph and rodent lineages, as well morphogenesis and adult tissue renewal. In recent years, analyses of as the molars of voles and a number of other animals, preserve their molecular signaling networks, together with new insights into cellular dental stem cells and are able to produce various cell lineages heterogeneity, have greatly improved our knowledge of the dynamic through adulthood to support the continuous formation of the crown epithelial-mesenchymal interactions that take place during tooth (Harjunmaa et al., 2014; Tapaltsyan et al., 2015). development and homeostasis. Here, we review recent progress in Owing to its easy accessibility in the oral cavity and to the wide the field of mammalian tooth morphogenesis and also discuss the availability of relevant mutant and transgenic animal lines, the tooth mechanisms regulating stem cell-based dental tissue homeostasis, provides a superb system to study the molecular mechanisms and regeneration and repair. These exciting findings help to lay a cellular functions that govern organogenesis during development and foundation that will ultimately enable the application of fundamental homeostasis. The epithelial-mesenchymal interactions that drive tooth research discoveries toward therapies to improve oral health. development, or odontogenesis, occur in many other ectodermal appendages, making the tooth a suitable model to answer questions KEY WORDS: Tooth development and homeostasis, Dental stem such as how an epithelium interacts with mesenchymal tissue to shape cell, Cell heterogeneity, Injury repair the features of an organ. Furthermore, studying how the regenerative capability of hypselodont teeth is maintained by dental stem cells Introduction during homeostasis and tissue repair can improve our knowledge of Teeth, which are anchored in maxillary and mandibular jaw bones, stem cell-driven organ renewal and facilitate the development of are the organs responsible for biting and gnawing. During evolution, therapeutic treatments for patients with dental diseases. tooth morphology tends to increase in complexity, while tooth In this Review, we summarize the latest progress in our number decreases. Indeed, fish and reptiles have larger numbers of understanding of how epithelial-mesenchymal signaling networks simple teeth, whereas mammalian teeth form cusps with complex regulate mammalian tooth development and adult tissue shapes that vary dramatically among different species. Mammals homeostasis. We explore the cellular and molecular mechanisms have four principal tooth types – incisors, canines, pre-molars and supporting mineralization as well as the response to injury, and we molars – that all vary in shape (Jernvall and Thesleff, 2012). These discuss how our view of dental stem cell behaviors has changed over variations in tooth shape are based on the location of the tooth in the the past few years, with some key findings related to the mouth, and are subject to strong selection during evolution in identification and heterogeneity of dental stem cells. Finally, we response to environmental pressures, such as diet. provide perspectives on the potential of technical advances that Teeth develop inside the jaw bone and then erupt postnatally into could help answer open questions regarding dental epithelial- the oral cavity. The upper portion of the mammalian tooth, which is mesenchymal interactions, as well as the migration, lineage plasticity exposed to the oral cavity, is known as the dental crown, and the and commitment of dental stem cells. portion buried inside the jaw bone is called the dental root. Based on the crown/root proportion, mammalian teeth can be divided An overview of early tooth development in mice into four main types: brachydont, mesodont, hypsodont and Early development of the rooted molar hypselodont. Brachydont teeth, commonly seen in omnivores The development of mammalian brachydont molars can be divided such as humans and mice, have a low crown-to-root ratio, with no into two main stages: shaping of the crown and formation of the crown extension into the jaw bones after eruption. Herbivorous root. In the mouse, molar development initiates at around embryonic mammals have evolved higher crowned mesodont and hypsodont day (E) 11.5. The first morphological sign of tooth development is a molars, in which a portion of the crown is reserved within the jaw thickening of the oral epithelium as it forms the dental placode bones, enabling these animals to contend with increased dental wear (Fig. 1A). In the following 48 h, the dental epithelium proliferates while processing abrasive food (Raia et al., 2011). Hypselodont, or and invaginates into the underlying mesenchyme and forms the dental lamina, and the dental mesenchyme condenses around the epithelium. Over the next 4 days, the epithelium continues to 1Program in Craniofacial Biology and Department of Orofacial Sciences, proliferate and elongate around the dental mesenchyme, thus University of California, San Francisco, CA 94143, USA. 2Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, shaping the tooth through the bud, cap and bell stages. CA 94143, USA. Early tooth development during the bud-to-cap transition requires signals from a transient signaling center named the *Author for correspondence ([email protected]) primary enamel knot (EK) (Jernvall et al., 2002). At the end of the O.D.K., 0000-0002-6254-7082 cap stage of molar development, the primary EK undergoes DEVELOPMENT 1 REVIEW Development (2020) 147, dev184754. doi:10.1242/dev.184754 A Molar development E11 E11.5 E12.5 E13.5 E14.5 E15.5 Initiation Placode Early bud Late bud Cap Early bell pEK OEE Dental RSDL cord Epithelium SR SR sEK Dental Condensing dental Mesenchyme CL papilla CL SR mesenchyme IEE OEE IEE Dental SR pulp CL CL B Brachydont: mouse molar E18.5 (late bell) PN7 Dental cord RSDL Ameloblasts sEK Enamel Dentin SR OEE IEE SR Odontoblasts Crown Dental pulp Dental Root CL CL ERM pulp HERS C Hypselodont: vole molar E18.5 (late bell) PN7 EKs? Enamel Ameloblasts Dentin Odontoblasts IEE IEE OEE SR icls SR OEE Dental HERS SR pulp icls CL CL Root Crown CL analog analog Fig. 1. Schematic of rodent molar development. (A) The initiation of mouse molar formation starts a little later than E11 with the thickening of dental epithelium (green). The tooth bud then forms via invagination of the dental epithelium into the underlying condensing mesenchyme (orange) at E12.5-E13.5. Signals sent from the primary (pEK) and secondary (sEK) enamel knots guide the formation and elongation of the cervical loop (CL), with the inner (IEE) and outer (OEE) enamel epithelium surrounding the stellate reticulum (SR). The rudimentary successional dental lamina (RSDL), which is a transient structure in most species, also begins to form at this time. (B) During the later stages of mouse molar development, the dental epithelium of the CL grows apically to become a transient structure called Hertwig’s epithelial root sheath (HERS) and the epithelial cell rests of Malassez (ERM), facilitating root formation. (C) During the later stages of molar development in voles, multiple intercuspal loops (icls) form and persist throughout the postnatal stages. These are then responsible for enamel deposition in between the icls. PN, postnatal day. apoptosis and is subsequently succeeded by secondary EKs at the canines, only one EK develops and no secondary EKs form, in bell stage (Fig. 1A) (Jernvall et al., 1998; Coin et al., 1999). Some contrast to what is observed in multicuspid molars, where of the primary EK cells are recruited during the formation of the multiple knots are seen (Vaahtokari et al., 1996; Jernvall and secondary EKs (Du et al., 2017), with the numbers and positions Thesleff, 2012). Although the mechanisms facilitating the of secondary EKs corresponding to the numbers and positions of transition from primary to secondary EKs are still unclear, the future tooth cusps. In monocuspid teeth such as incisors and proper formation of secondary EKs relies on the primary EK. For DEVELOPMENT 2 REVIEW Development (2020) 147, dev184754. doi:10.1242/dev.184754 example, the size of the primary EK can affect the position of the At the cap stage at around E14.5, incisor dental epithelial tissue secondary EKs (Pispa et al., 1999; Ohazama et al., 2004). expands longitudinally, receiving signals from the de novo-formed During the cap-to-bell transition, continuous folding divides the EK that replaces the IK (Ahtiainen et al., 2016) (Fig. 2). Distinct to dental epithelium into inner and outer enamel epithelium (IEE and the cell recruitment happening during the transition from primary to OEE). Mesenchymal cells adjacent to the IEE form the dental secondary EK formation during molar development, progeny of the papilla, whereas cells around the OEE form the dental
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