Tooth and jaw: molecular mechanisms of patterning in the first branchial arch

The mammalian jaw apparatus is ultimately derived from the first branchial arch derivatives, the maxillary and mandibular processes, and composed of a highly specialised group of structures. Principle amongst these are the skeletal components of the mandible and maxilla and the teeth of the mature dentition. Integral to the development of these structures are signalling interactions between the stomodeal ectoderm and underlying neural crest-derived ectomesenchymal cells that populate this region. Recent evidence suggests that in the early mouse embryo, regionally restricted expression of homeobox-containing genes, such as members of the Dlx, Lhx and Gsc classes, are responsible for generating early polarity in the first branchial arch and establishing the molecular foundations for patterning of the skeletal elements. Teeth also develop on the first branchial arch and are derived from both ectoderm and the underlying ectomesenchyme. Reciprocal signalling interactions between these cell populations also control the odontogenic developmental programme, from early patterning of the future dental axis to the initiation of tooth development at specific sites within the ectoderm. In particular, members of the Fibroblast growth factor (Fgf), Bmp, Hedgehog and Wnt families of signalling molecules induce regionally restricted expression of downstream target genes in the odontogenic ectomesenchyme. Finally, the processes of morphogenesis and cellular differentiation ultimately generate a tooth of specific class. Many of the same genetic interactions that are involved in early tooth development mediate these effects through the activity of localised signalling centres within the developing tooth germ.     

Patterning of the murine dentition by homeobox genes

Homeobox genes have been shown to be important for the regulation of pattern formation of many systems during embryogenesis. Overlapping domains of Hox gene expression in the paraxial mesoderm have been suggested to create a combinatorial code of expression (Hox code) specifying the structures of individual segments such as the vertebrae. Hox genes are not expressed in the neural crest cells contributing to tooth formation, and so a Hox code can not be involved in patterning the dentition. It has previously been proposed that other, non-Hox homeobox genes may pattern the dentition. Expression data in this paper shows that there is a pattern of overlapping domains of homeobox gene expression in facial mesenchyme prior to the initiation of tooth development. We propose that expression of these genes constitutes an odontogenic homeobox code which patterns the dentition.     

Morphogenetic fields within the human dentition: a new, clinically relevant synthesis of an old concept

This paper reviews the concept of morphogenetic fields within the dentition that was first proposed by Butler (Butler PM. Studies of the mammalian dentition. Differentiation of the post-canine dentition. Proc Zool Soc Lond B 1939;109:1-36), then adapted for the human dentition by Dahlberg (Dahlberg AA. The changing dentition of man. J Am Dent Assoc 1945;32:676-90; Dahlberg AA. The dentition of the American Indian. In: Laughlin WS, editor. The Physical Anthropology of the American Indian. New York: Viking Fund Inc.; 1951. p. 138-76). The clone theory of dental development, proposed by Osborn (Osborn JW. Morphogenetic gradients: fields versus clones. In: Butler PM, Joysey KA, editors Development, function and evolution of teeth. London: Academic Press, 1978. p. 171-201), is then considered before these two important concepts are interpreted in the light of recent findings from molecular, cellular, genetic and theoretical and anthropological investigation. Sharpe (Sharpe PT. Homeobox genes and orofacial development. Connect Tissue Res 1995;32:17-25) put forward the concept of an odontogenic homeobox code to explain how different tooth classes are initiated in different parts of the oral cavity in response to molecular cues and the expression of specific groups of homeobox genes. Recently, Mitsiadis and Smith (Mitsiadis TA, Smith MM. How do genes make teeth to order through development? J Exp Zool (Mol Dev Evol) 2006; 306B:177-82.) proposed that the field, clone and homeobox code models could all be incorporated into a single model to explain dental patterning. We agree that these three models should be viewed as complementary rather than contradictory and propose that this unifying view can be extended into the clinical setting using findings on dental patterning in individuals with missing and extra teeth. The proposals are compatible with the unifying aetiological model developed by Brook (Brook AH. A unifying aetiological explanation for anomalies of tooth number and size. Archs Oral Biol 1984;29:373-78) based on human epidemiological and clinical findings. Indeed, this new synthesis can provide a sound foundation for clinical diagnosis, counselling and management of patients with various anomalies of dental development as well as suggesting hypotheses for future studies.     

Dental enamel formation and its impact on clinical dentistry

The nature of tooth enamel is of inherent interest to dental professionals. The current-day clinical practice of dentistry involves the prevention of enamel demineralization, the promotion of enamel remineralization, the restoration of cavitated enamel where demineralization has become irreversible, the vital bleaching of dental enamel that has become discolored, and the diagnosis and treatment of developmental enamel malformations, which can be caused by environmental or genetic factors. On a daily basis, dental health providers make diagnostic and treatment decisions that are influenced by their understanding of tooth formation. A systemic condition during tooth development, such as high fever, can produce a pattern of enamel defects in the dentition. Knowing the timing of tooth development permits estimates about the timing of the disturbance. The process of enamel maturation continues following tooth eruption, so that erupted teeth can become less susceptible to decay over time. Mutations in the genes encoding enamel proteins lead to amelogenesis imperfecta, a collection of inherited diseases having enamel malformations as the predominant phenotype. Defects in the amelogenin gene cause X-linked amelogenesis imperfecta, and genes encoding other enamel proteins are candidates for autosomal forms. Here we review our current understanding of dental enamel formation, and relate this information to clinical circumstances where this understanding may be particularly relevant.     

Tooth size in 47,XYY males: evidence for a direct effect of the Y chromosome on growth

Abstract — Mean values of deciduous and permanent tooth dimensions were compared between 47, XYY males and control subjects to clarify the role of the Y chromosome in dental development. Tooth size was generally larger in the 47, XYY sample, although the increase in size was not uniform throughout the dentition. The Y chromosome appears to have a direct effect on tooth size which may be due to a specific gene (or genes) or may be related to a more non-specific effect of heterochromatin on cellular activity.     

The House Shrew,Suncus murinus,as a Model Organism to Investigate Mammalian Basal Condition of Tooth Development

Mammalian dentition is characterized by regional differentiation into incisors, canines, premolars and molars in each jaw quadrant (heterodonty), and tooth replacement once during the lifetime (diphyodonty). Despite their significance in various research fields, little is known about the developmental mechanisms regulating tooth type (class) determination and diphyodont tooth replacement. The mouse, the most popular laboratory animal, is not appropriate for the investigation of heterodonty and diphyodonty, because of its highly specialized dentition. The house shrew, Suncus murinus, has been suggested to be a potentially excellent model organism to study the mammalian basal condition of tooth development. Using three-dimensional (3-D) reconstructions of dental epithelium from serial histological sections, and Sonic hedgehog (Shh) expression patterns, we have precisely located the tooth-forming regions of all tooth types in the developing jaws of the house shrew. The incisor region in the upper jaw is found to extend across the boundary between the frontonasal and maxillary processes. The molar-forming region is later added distal to the first demarcated tooth-forming regions by secondary extension of the dental lamina. Furthermore, we have elucidated the replacement pattern of the deciduous dentition by succession and addition (accession) of the permanent teeth in the house shrew. On the basis of new knowledge on tooth development in the house shrew, we discuss the developmental mechanisms regulating tooth type determination and diphyodont tooth replacement, and consider future prospects in the field.     

MSX1mRNA在犬恒牙牙根发育过程中的表达及意义

目的：观察同源异形盒基因MSX1在狗年龄恒牙牙根发育过程中的时空表达，初步探讨其对牙根形态形成的调控作用。方法：采用原位杂交技术，对犬恒牙牙根不同发育时期MSX1mRNA的表达进行观察。结果：在牙根发育不同时期内，MSX1mRNA不仅在牙乳头、牙囊组织及成牙本质细胞中有阳性表达，而且在牙附着组织，如成牙骨质细胞、上皮根鞘、牙周组织及根牙槽骨组织中也有表达。结论：MSX1作为牙齿发育过程中重要的转录因子，参与牙根形态发育的调控作用。     

Genetic,environmental and epigenetic influences on variation in human tooth number,size and shape

The aim of this review is to highlight some key recent developments in studies of tooth number, size and shape that are providing better insights into the roles of genetic, environmental and epigenetic factors in the process of dental development. Advances in molecular genetics are helping to clarify how epigenetic factors influence the spatial and temporal regulation of the complex processes involved in odontogenesis. At the phenotypic level, the development of sophisticated systems for image analysis is enabling new dental phenotypes to be defined. The 2D and 3D data that are generated by these imaging systems can then be analysed with mathematical approaches, such as geometric morphometric analysis. By gathering phenotypic data and DNA from twins, it is now possible to use ‘genome-wide’ association studies and the monozygotic co-twin design to identify important genes in odontogenesis and also to clarify how epigenetic and environmental factors can affect this process. Given that many of the common dental anomalies affecting the human dentition are interrelated, apparently reflecting pleiotropic genetic effects, the discoveries and new directions described in this paper should have important implications for clinical dental practice in the future.     

Genetic and environmental influences on human dental variation: a critical evaluation of studies involving twins

Utilising data derived from twins and their families, different approaches can be applied to study genetic and environmental influences on human dental variation. The different methods have advantages and limitations and special features of the twinning process are important to consider. Model-fitting approaches have shown that different combinations of additive genetic variance (A), non-additive genetic variance (D), common environmental variance (C), and unique environmental variance (E) contribute to phenotypic variation within the dentition, reflecting different ontogenetic and phylogenetic influences. Epigenetic factors are also proposed as important in explaining differences in the dentitions of monozygotic co-twins. Heritability estimates are high for most tooth size variables, for Carabelli trait and for dental arch dimensions, moderate for intercuspal distances, and low for some occlusal traits. In addition to estimating the contributions of unmeasured genetic and environmental influences to phenotypic variation, structural equation models can also be used to test the effects of measured genetic and environmental factors. Whole-genome linkage analysis, association analysis of putative candidate genes, and whole genome association approaches, now offer exciting opportunities to locate key genes involved in human dental development.     

Development of heterodont dentition in house shrew (Suncus murinus)

Mammalian heterodont dentition comprises incisors, canines, premolars, and molars. Although there has been intensive research, the patterning of these specific tooth types has not yet been elucidated. In order for the gene expression data to be linked with tooth type determination, it is first necessary to determine precisely the incisor-, canine-, premolar-, and molar-forming regions in the jaw primordia. To accomplish this, we studied dentition development in the house shrew (Suncus murinus), which has retained all the tooth types, using three-dimensional reconstructions from serial histological sections and the Sonic hedgehog (Shh) expression patterns. Before the appearance of morphological signs of odontogenesis, Shh expression localized to the presumptive tooth-forming regions, in which the mesial and distal expression domains corresponded to the incisor- and premolar-forming regions, respectively. The upper incisor region was found to extend across the boundary between the frontonasal and the maxillary processes. The canine-forming regions later appeared in the intermediate portions of the maxillary and the mandibular processes. The molar-forming regions later appeared distal to the initially demarcated tooth-forming regions by secondary extension of the distal ends. The demarcation visualized by the Shh expression pattern in the jaw primordia of the house shrew probably represents the basic developmental pattern of mammalian heterodont dentition.     

Genetic susceptibility to dental caries on pit and fissure and smooth surfaces

Carious lesions are distributed nonuniformly across tooth surfaces of the complete dentition, suggesting that the effects of risk factors may be surface-specific. Whether genes differentially affect caries risk across tooth surfaces is unknown. We investigated the role of genetics on two classes of tooth surfaces, pit and fissure surfaces (PFS) and smooth surfaces (SMS), in more than 2,600 subjects from 740 families. Participants were examined for surface-level evidence of dental caries, and caries scores for permanent and/or primary teeth were generated separately for PFS and SMS. Heritability estimates (h(2), i.e. the proportion of trait variation due to genes) of PFS and SMS caries scores were obtained using likelihood methods. The genetic correlations between PFS and SMS caries scores were calculated to assess the degree to which traits covary due to common genetic effects. Overall, the heritability of caries scores was similar for PFS (h(2) = 19-53%; p < 0.001) and SMS (h(2) = 17-42%; p < 0.001). Heritability of caries scores for both PFS and SMS in the primary dentition was greater than in the permanent dentition and total dentition. With one exception, the genetic correlation between PFS and SMS caries scores was not significantly different from 100%, indicating that (mostly) common genes are involved in the risk of caries for both surface types. Genetic correlation for the primary dentition dfs (decay + filled surfaces) was significantly less than 100% (p < 0.001), indicating that genetic factors may exert differential effects on caries risk in PFS versus SMS in the primary dentition.     

Molecular control of odontogenic patterning: positional dependent initiation and morphogenesis

We have previously proposed that the patterning of the mammalian dentition is determined by an odontogenic homeobox code, whereby positional specification of odontogenic ectomesenchymal cell populations in a given region of the first branchial arch are determined by the combination of different homeobox genes expressed, described in detail in (1). Here we describe the first functional evidence for such a mechanism, and show that development of different types of teeth is controlled by independent genetic pathways. We suggest a mechanism whereby patterning is determined by position dependent control of tooth germ initiation, and propose that the pathway of morphogenesis is directly linked to the early mesenchymal expression of homeobox genes.     

Increased apoptosis during morphogenesis of the lower cheek teeth in tabby/EDA mice

In wild-type (WT) mice, epithelial apoptosis is involved in reducing the embryonic tooth number and the mesial delimitation of the first molar. We investigated whether apoptosis could also be involved in the reduction of tooth number and the determination of anomalous tooth boundaries in tabby (Ta)/EDA mice. Using serial histological sections and computer-aided 3D reconstructions, we investigated epithelial apoptosis in the lower cheek dentition at embryonic days 14.5-17.5. In comparison with WT mice, apoptosis was increased mainly mesially in Ta dental epithelium from day 15.5. This apoptosis showed a similar mesio-distal extent in all 5 morphotypes (Ia,b,c and IIa,b) of Ta dentition and eliminated the first cheek tooth in morphotypes IIa,b. Apoptosis did not appear to play any causal role in positioning inter-dental gaps. Analysis of the present data suggests that the increased apoptosis in Ta mice is a consequence of impaired tooth development caused by a defect in segmentation of dental epithelium.