- Yu Jian
[Abstract] Tooth development begins with reciprocal signaling interactions between the neural-crest-derived ectoderm epithelium and the ectomesenchyme cells. In recent two decades, a mass of signaling molecules and transcription factors which are crucial for these processes have been confirmed, among which Wnt signaling pathway plays a key role in the regulation of embryo tooth development. This article reviews the research advancements on the function of Wnt signaling pathway during the course of embryo and postnatal tooth development as well as relevant molecular biological mechanism, providing new inspiration for understanding the mechanism of tooth development and associated disease.
[Key words] Tooth development, Wnt signaling pathway, Mechanism.
Tooth development starts with reciprocal signaling interactions between the ectoderm epithelium and the ectomesenchyme cells derived from the neural crest. The first sign of tooth development is acknowledged as the thickening of the oral epithelium, then the epithelium begins to invaginate into the underlying mesenchyme to form buds. Central features of tooth morphogenesis are the generation of the epithelial placode, the budding of the epithelium, the condensation of mesenchyme around the bud and the folding and growth of the epithelium generating the shape of the tooth crown. The communication between the two tissues, the epithelium and the mesenchyme, is the key regulatory mechanism on governing tooth development. The language that cells use for communication is composed of mainly secreted signal molecules and growth factors. The most studied and universal signals are members of four conserved families, transforming growth factor beta (TGF-b, includes BMPs and activins), fibroblast growth factor (FGF), sonic hedgehog (Shh, in sonic hedgehog teeth only) and Wnt.
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Wnt proteins mediate the transduction of at least three major signaling pathways that play central roles in many early and late developmental decisions. Wnt genes regulate cell growth, development, migration and differentiation. Wnt genes encode secreted glycoproteins, usually 350–400 amino acids in length. The degree of sequence identity in Wnt proteins is minimally 18%, including a conserved pattern of 23-24 cysteine residues, in addition to other invariant amino acids. Wnt signals transduce many distinct pathways, three of which have been the most studied these past decades. Among these three major pathways, the first to be elucidated was the Wnt/β-catenin pathway, often called the “canonical” Wnt pathway. After that, several others called “non-canonical” Wnt pathways were discovered; these involve many of the same components used by the canonical pathway but with molecular relationships between these components that are altered relative to the canonical pathway, or they utilize different transducing molecules. The most studied of these non-canonical Wnt pathways are the planar cell polarity (PCP) pathway and the Wnt-calcium pathway[4, 5].
In this article, it will primarily focus on Wnt signaling pathway, paying particular attention to recent insights. Research advances on the function of Wnt signaling pathway during the course of embryo and postnatal tooth development as well as relevant molecular biological mechanism are reviewed, offering new principles for understanding the mechanism of tooth development and associated disease.
1. The role of Wnt signaling pathway in the initial stage of dental germ
The early arrest of tooth development in Lef1 mutant mice suggested that Wnt signaling pathway may have an essential effect in early tooth development. Wnt10b was expressed especially in mesial cells of the molar dental epithelial thickening and not in the oral epithelium. Wnt5a exhibited the similar graded proximo-distal (P-D) increased in the expression in mandibular and maxillary mesenchymal expression as MFrzb1 and Mfrp2. Wnt4 transcripts together with the Wnt receptor MFz6 exhibited uniform expression in the oral, dental and head epithelium. Wnt3 and Wnt7b were expressed in the oral epithelium but were notably absent from the dental epithelium.
Fjeld K et al. found that members of the Dickkopf (Dkk) family modulated the Wnt signaling pathway by binding to the Wnt receptor complex. Dkk1 was prominently expressed in the distal, incisor-bearing mesenchyme area of the mandibular process during the initial stages of tooth formation. Dkk2 was discovered in the dental papilla, whereas Dkk3 was specifically expressed in the putative epithelial signaling centers, the primary and secondary enamel knots.
By performing tissue recombinant experiments and analyzing the effects of signaling molecules, Kettunen P found that in early oral and dental epithelia, which instructed tooth formation, and epithelial Wnt4 induced Sema3a expression in the presumptive dental mesenchyme before the arrival of the first dental nerve fibers. By analyzing Sema3a and its receptor Npn1 knockout mouse embryos, they found that Sema3a regulated dental trigeminal axon navigation and patterning, as well as the timing of the first mandibular molar innervation, and that the effects of Sema3a appeared to be mediated by Npn1 presented in the axons.
Wnt7b acted to repress Shh expression in oral ectoderm, thus maintained the boundaries between oral and dental ectodermal cells. Implantation of beads soaked in Shh protein into Wnt7b-infected explants resulted in complete rescue of tooth development, confirming that the repressive action of Wnt7b specifically affected Shh signaling.
2. The role of Wnt signaling pathway in bug stage of dental germ
Using nuclear localization of β-catenin, however, Wnt activity was found not only in the tooth bud epithelium but also the underlying mesenchyme. Wnt/β-catenin signaling was active throughout tooth development.
A gain of function mutation in epithelial β-catenin resulted in expanded expression of several key regulatory genes. Conversely, expression of these key dental regulators was disrupted when epithelial and mesenchymal Wnt/β-catenin signaling was inhibited soon after tooth initiation in Dkk1 expressing embryos, resulting in arrested development at the early bud stage. These data indicated that Wnt/β-catenin signaling was required within dental epithelial cells for tooth development beyond the lamina-early bud stage. The mechanism underlying arrested development in Dkk1 expressing embryos appeared to involve loss of expression of Bmp4, Msx1, and Msx2. Consistent with this model, tooth development arrested at a similar stage in Msx1−/− Msx2−/− mice and Wnt-inhibited mice.
Lef1 and PITX2 function in the Wnt signaling pathway by recruiting and interacting with β-catenin to activate target genes. PITX2 isoforms regulated the Lef1 promoter, and β-catenin synergistically enhanced activation of the Lef1 promoter in combination with PITX2 and Lef1 isoforms. PITX2 enhanced endogenous expression of the full-length β-catenin-dependent Lef1 isoform (Lef-1 FL) while decreasing expression of the N-terminally truncated β-catenin-independent isoform. Recombinations of epithelial and mesenchymal tissues from developing teeth of wild-type and Lef1−/− embryos showed that Lef1 was required only transiently in epithelium in a tissue-nonautonomous manner, which was rather unexpected for a component of a signal reception pathway.
In addition, Fgf4 beads induced rapidly the expression of Fgf3 in dental mesenchyme and that both epithelial and mesenchymal Fgf proteins induced the delayed expression of Shh in the epithelium. Taken together, these data indicated that a single target of Lef1 can account for the function of Lef1 in tooth development and for a relay of a Wnt signal reception to a cascade of Fgf signaling activities, allowing for a sequential and reciprocal communication between epithelium and mesenchyme.
3. The role of Wnt signaling pathway in cap stage of dental germ
At the cap stage of dental germ the primary enamel knots were evident. Expression of Lef1, Wnt3, Wnt6, Wntl0 and MFz6 were seen exclusively in the primary enamel knots. Wnt5a and MFrzb1 showed strong expression in dental papilla mesenchyme. At the cap stage Dkk1 and Dkk2 transcripts were observed in the cervical region of the mesenchymal dental papilla and in the dental follicle, respectively, whereas Dkk3 mRNAs were specifically expressed in the epithelial PEK, mostly at the buccal side.
4. The role of Wnt signaling pathway in bell stage of dental germ
Inducible Dkk1 expression after the cap stage caused formation of blunted molar cusps, downregulation of the enamel knot marker p21, and loss of restricted ectodin expression, revealing requirements for Wnt activity in maintaining secondary enamel knots. The inhibitory effect of Wise on Wnt signaling was further examined by assaying secondary head induction, which could be induced by simultaneous inhibition of both BMP and Wnt signaling.
Ectodin, a secreted bone morphogenetic protein (BMP) inhibitor, is expressed as a ‘‘negative’’ image of mouse enamel knots. Furthermore, the ectodin-deficient mice have enlarged enamel knots, highly alters cusp patterns, and extra teeth. Unlike in normal teeth, excessive BMP accelerates patterning in ectodin-deficient teeth. The ectodin is critical for robust spatial delineation of enamel knots and cusps. These data placed Wnt/β-catenin signaling upstream of key morphogenetic signaling pathways at multiple stages of tooth development and indicated that tight regulation of this pathway was essential both for patterning tooth development in the dental lamina and controlling the shape of individual teeth.
At the early bell stage, Wnt reporter activity localized to the developing molar cusps and by the late bell stage was present asymmetrically in the epithelial enamel knots of developing molar cusps. Wnt/β-catenin signaling was active at multiple stages of tooth development. Mutation of β-catenin to a constitutively active formed in oral epithelium caused formation of large, misshapen tooth buds and ectopic teeth, and expanded expression of signaling molecules important for tooth development. Conversely, expression of key morphogenetic regulators including Bmp4, Msx1, and Msx2 was downregulated in embryos expressing the secreted Wnt inhibitor Dkk1, which blocked signaling in epithelial and underlying mesenchymal cells.
5. The role of Wnt signaling pathway in secretory stage of dental germ
Dspp and Wnt10a were co-localized in the differentiated odontoblasts. Wnt10a and cell to matrix interactions played an important role for odontoblast differentiation and that Wnt10a linked tooth morphogenesis and the differentiation of odontoblasts. In addition to being expressed in the developing mandibular bone, Dkk1 was prominently up-regulated in the preodontoblasts and the expression continued in the secretory odontoblasts. In contrast, Dkk3 was transiently expressed in the ameloblasts before enamel matrix secretion. When comparing the Dkk1-Tg first molars with the age-matched controls, it was observed striking differences in the appearance of the dentin tubules, with the tubular processes being sharply reduced and disorganized. Analysis of quantitative data showed a significant reduction of dentinal tubule number in Dkk1-Tg mice.
6. The role of Wnt signaling pathway in postnatal tooth development
Hertwig’s epithelial root sheath (HERS) is very important for root development. Syndecan-1 is cell surface heparan sulfate proteoglycans (HSPGs) and it plays an important role for Wnt/β-catenin signaling pathway as a coreceptor.
Genetic data from humans and mice revealed that the formation of cementum was sensitive to intra- and extracellular phosphate/pyrophosphate distribution. Studies of the temporal effects of extracellular phosphate on global patterns of gene expression in a line of immortalized mouse cementoblasts indicated that extracellular phosphate altered the expression of genes comprising several gene ontology (GO) groups, including Wnt signaling. The analysis of existing data demonstrated a role for Wnt signaling in bone formation or remodeling and tooth development. In this regard, the ability of ePi to alter the expression pattern of genes involved in Wnt signaling is of interest. The expression of one secreted blocker of canonical Wnt signaling, Sfrp4, was enhanced, while that of another, Wif1, was depressed. Two Wnt signaling genes, Wnt10b and Wnt4, were diminished, as was the level of the membrane-bound inhibitor Dkk 3 (Dickkoff).
Tumors associated with osteomalacia elaborated the novel factor(s), phosphatonin(s), which caused phosphaturia and hypophosphatemia by cAMP-independent pathways. Results showed that secreted frizzled-related protein-4 (sFRP-4), a protein highly expressed in such tumors, was a circulating phospha-turic factor that antagonized renal Wnt-signaling.
Studies using Wnt reporters have revealed discrepancies between nuclear B-catenin and Wnt reporter expression during tooth development, and so it was wished to clarify Wnt responsiveness using the Axin2 reporter during early stages of tooth development. Previous studies have also concentrated on molar development and so expression in the incisors was also investigated. In addition, because canonical Wnt activity has so far only been investigated up to the bell stage of dental germ, it was investigated expression at later stages of tooth development to gain an insight into the possible later roles of canonical Wnt signaling in tooth development.
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Canonical Wnt activity was completely absent at all stages investigated in the developing ameloblasts in molars and incisors, while presented in areas of the epithelium where ameloblasts did not form (molars-enamel–free areas, incisors–lingual side and tip of tooth). This indicated that canonical Wnt activity did not play a role in the terminal differentiation of ameloblasts and may, in fact, act to keep epithelial cells in a proliferative state.
In conclusion, Wnt signaling pathway plays a vital role in the development of multiple ectodermal appendages including teeth. As the regulation of Wnt signaling pathway emerges during the course of embryo and postnatal tooth development, it is of great significance to study the exact molecular biological mechanism. Moreover, more efforts should be made so as to achieve a better understanding for tooth development and associated disease, and new strategies which utilized to activate this pathway for tooth regeneration are needed as well.
 Lohi M, Tucker AS, Sharpe PT. Expression of Axin2 indicates a role for canonical Wnt signaling in development of the crown and root during pre- and postnatal tooth development. Dev Dyn 2010, 239(1): 160-167.
Kettunen P, Loes S, Furmanek T, et al. Coordination of trigeminal axon navigation and patterning with tooth organ formation: epithelial-mesenchymal interactions, and epithelial Wnt4 and Tgfbeta1 regulate semaphorin 3a expression in the dental mesenchyme. Development 2005, 132(2): 323-334.
Yamashiro T, Zheng L, Shitaku Y, et al. Wnt10a regulates dentin sialophosphoprotein mRNA expression and possibly links odontoblast differentiation and tooth morphogenesis. Differentiation 2007, 75(5): 452-462.
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