Mammalian tooth development involves highly regulated reciprocal signaling interactions between the epithelium and mesenchyme. Classic tissue recombination experiments demonstrated that, although tooth inductive signals arise initially in the embryonic oral ectoderm, tooth inductive potential shifts from ectoderm to mesenchyme at the early tooth bud stage, with the developing tooth mesenchyme acquiring capability of inducing tooth organogenesis even when combined with non-dental epithelium (Kollar and Baird, 1970; Kollar and Fisher, 1980; Lumsden, 1988; Mina and Kollar, 1987; Ruch et al., 1973). As development proceeds, mesenchymal signals induce formation of an epithelial signaling center, termed the primary enamel knot (PEK), in the distal region of the tooth bud, which in turn drives tooth morphogenesis through the ‘cap’ and ‘bell’ stages by signaling into both the dental epithelium and mesenchyme. Many signaling molecules, including members of the Bmp, Fgf and Wnt families and Shh, are expressed during early tooth development (reviewed by Jernvall and Thesleff, 2000; Tucker and Sharpe, 2004; Zhang et al., 2005). Among these, Bmp4 exhibits an expression pattern coinciding with the shift of odontogenic
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and transformation of incisors into molars has been achieved in vitro by modulation of BMP signalling and thereby the relative expression domains of homeobox genes Barx-1 and Msx-1 (Tucker et al., 1998). Antagonistic signalling by FGF and BMP ligands in oral ectoderm appears to determine the initial patterns of gene expression in mesenchyme that specify odontogenic potential and tooth identity (Peters and Balling, 1999; Tucker et al., 1998). Nkx2- 3 was initially expressed broadly in ectoderm of the first pair of branchial arches, although by E10.0 had become restricted to paired narrow ectodermal stripes, presumably odontogenic epi- thelium. By E13.5, expression was seen in tooth anlage of the lower jaw, with highest levels in the molar regions. The mechanism of this restriction has not been defined, although we can reasonably expect, drawing on parallels from heart and visceral mesoderm (Harvey, 1996; Smith et al., 2000; Sparrow et al., 2000), a role for BMP signalling in induction or maintenance of the Nkx2-3 pattern. The individuality in the pattern of tooth cusps defines the identity of molars. Cusp formation is controlled by enamel knots, transient ectodermal signalling centres that regulate the balance between cell proliferation and cell death in the ectoderm, and subtle differ- ences in these responses determines the final profile of each tooth (Peters and Balling, 1999). The loss of cusps in the lower molars of Nkx2-3 lacZ∆HD/lacZ∆HD mice suggests a role for Nkx2-3 in the latter stages of tooth morphogenesis, perhaps in regulating the prolifera- tive response of ectoderm to FGFs expressed by mesenchyme (Peters and Balling, 1999). Nkx2-3 could also be necessary for formation of enamel knots that orchestrate cusp morphogenesis. An alternative hypothesis is that terminal differentiation of amelo- blasts is affected, leading to weak enamel which becomes eroded by mastication. The restriction in Nkx2-3 expression and function to the lower jaw highlights the fact that different patterning mecha- nisms act in morphogenesis of mandibular and maxillary molars. This is also evident in mice lacking the homeogenes Dlx1 and Dlx2, where only maxillary teeth are affected (Qiu et al., 1997). The availability of a host of markers for the multiple stages of tooth development (Peters and Balling, 1999) will facilitate further analy- sis of this dichotomy.
Previous data have shown that components of the Notch signalling pathway are expressed in developing mouse teeth. Expression of Notch1, Notch2, Notch3 (Mitsiadis et al., 1995a), Dll1 (Mitsiadis et al., 1998a), Jag1 (Mitsiadis et al., 1997) and Jag2 (Mitsiadis et al., 2005; Valsecchi et al., 1997) in developing teeth prefigures the subdivision of the epithelium into ameloblastic (capable of enamel-matrix synthesis) and non-ameloblastic regions already at the initiation stage. This becomes obvious during cytodifferentiation, in which Notch receptors and ligands show complementary expression patterns: Notch1 expression is confined to the stratum intermedium, whereas Dll1 and Jag2 are expressed in the adjacent inner dental epithelium layer (Mitsiadis et al., 1998a; Mitsiadis et al., 2005; Valsecchi et al., 1997). Similarly, in dental mesenchyme, Dll1 is expressed in differentiating odontoblasts, whereas the Notch genes are predominantly expressed in the sub-odontoblastic layer (Mitsiadis et al., 1998a). These results suggest that Notch receptors and ligands control tooth morphogenesis and influence differentiation events. However, little information exists about the in vivo biological role of Notch signalling during odontogenesis. This is mainly due to the early embryonic death (at E11-12) of Notch1 (Swiatek et al., 1994), Notch2 (Hamada et al., 1999; McCright et al., 2001), Jag1 (Xue et al., 1999) and Dll1 (Hrabe de Angelis et al., 1997) homozygous mice.
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Fig. 3. (Right) Developmental expression of Smad2 during tooth morphogenesis in vivo. (A) At the dental lamina stage, Smad2 was expressed within the dental epithelium (arrow) and mesenchyme (*). (B) At the bud stage, Smad2 was present within the dental epithelium and CNC-derived mesenchyme. Notice that majority of the staining was in the cytoplasm. (C) Using antibody to localize the expression of phosphorylated Smad2 (PS2) at the late bud stage, we showed that activated Smad2 was present within dental epithelium and mesenchyme. Insert = positive PS2 staining within dental epithelium (arrow points to positive nucleus staining with anti-PS2). (D) At the cap stage, Smad2 was associated with inner enamel organ epithelium and CNC-derived dental mesenchyme while outer enamel organ epithelium (double arrow) also showed some positive staining. Insert shows positive PS2 staining within dental epithelium. (E) At the bell stage, Smad2 was present within inner enamel organ epithelium, stellate reticulum (SR) and dental mesenchyme (*). (F) In Smad3 null mutant sample, Smad2 was detected at the identical location where endogenous Smad3 was expressed in this cap stage tooth organ (see Fig. 3D). (G,H) In situ hybridization demonstrated the spatial and temporal distribution of Smad2 mRNA during tooth morphogenesis. Positive staining is in deep purple. Specifically, Smad2 was localized to dental epithelium and mesenchyme at E13.5 (G). Later on, Smad2 was mainly localized to the inner enamel epithelium and dental mesenchyme at the cap stage (H).
The temporal and spatial combination of signals determines neural crest cell fates. Previous studies have demonstrated that the combinatorial activity of the BMP and WNT signaling pathways promotes sensory neuron fate during early neural crest cell development (Kléber et al., 2005). After migration, neural crest- derived dental mesenchymal cells still possess the potential to differentiate into dentin-secreting odontoblasts as well as chondrocyte-like and osteoblast-like cells during craniofacial development (Chai et al., 2000; Chung et al., 2009; Yamazaki et al., 2007). Here, we have demonstrated that SMAD4 is indispensable for odontoblast differentiation during tooth development and that loss of Smad4 in the dental mesenchyme results in ectopic osteoblast differentiation and bone formation via WNT pathway upregulation. Thus, the interplay between the TGF/BMP and WNT signaling pathways also functions to ensure proper cell fate determination during postmigratory neural crest cell development and organogenesis. From a clinical perspective, our study might help to provide etiological clues of heritable dentin disorders and suggest novel therapeutically useful strategies and candidates for future investigation.
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Epithelial morphogenesis was impaired in Foxi3 cKO mice To determine the stage of molar morphogenesis when the Foxi3 cKO tooth phenotype arises, we analyzed the histology of control and mutant molars from the M1 initiation onwards, as Foxi3 is already expressed in the epithelium in the molar placode and bud (Shirokova et al., 2013). At embryonic day (E) 12.5, the Foxi3 cKO placode was smaller compared with controls, and the suprabasal epithelium appeared especially poorly developed (Fig. 2A,B). At E13.0 and E13.5, budding morphogenesis was impaired in Foxi3 cKO (Fig. 2C-F). Both the dental cord and the stellate reticulum were missing from Foxi3 cKO molars (Fig. 2E-J). Cervical loops formed in Foxi3 cKO, but they were smaller in size than controls (Fig. 2G,H). At E16, the IEE did not show normal folding, indicating that the shape of the crown was not forming correctly (Fig. 2I-L). At E18, some embryos showed normal M3 bud formation despite the fusion of M1 and M2 (Fig. 2M,N). Mesenchymal condensation and ameloblast differentiation appeared normal in Foxi3 cKO embryos (Fig. 2). In postnatal day (P) 8 molar crown, there was secreted enamel and dentin, and root formation had been initiated normally (Fig. 2O,P). We analyzed the efficiency of the Cre-driver used and noticed mosaic Foxi3 expression in the Foxi3 cKO molars at E12.5 (Fig. S2A-C). At later stages (E13.5 and E14.5), qRT-PCR and in situ hybridization confirmed the downregulation of Foxi3 expression (Fig. 5A; Fig. S2D,E). In conclusion, loss of Foxi3 affects several epithelial cell populations in the developing molar and impairs tooth morphogenesis.
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ABSTRACT The enamel knot (EK), located in the center of cap-stage tooth germs, is a transitory cluster of non-dividing epithelial cells, eventually linked to the outer dental epithelium by the enamel septum (ES). It might act as a signaling center providing positional information for tooth morphogenesis and could regulate the growth of tooth cusps through the induction of secondary signaling EKs. The EK undergoes apoptosis, which could constitute a mechanism whereby the signaling functions of this structure are terminated. Recently, we demonstrated the segregation of 5-bromo-2'-deoxyuridine (BrdU) negative inner dental epithelial (IDE) cells of the EK into as many individual groups of cells as cusps will form and suggested a morphogenetic role for these particular IDE cells. Using Z-VAD-fmk, a specific caspase inhibitor, apoptosis in the primary EK of first mouse lower cap-staged molars and lower incisors cultured in vitro was abrogated. No obvious histologi- cal alterations were observed in the incisors, whereas a prominent EK and an ES connecting the outer dental epithelium (ODE) and the BrdU negative IDE cells capping cusp L2 were observed in the molars. EK specific transcription (Shh, Msx-2, Bmp-2, Bmp-4) was down-regulated in the body of these structures with the exception of the associated IDE cells. In these experimental conditions, segregation of non-dividing transcriptionally active IDE cells occurred and a normal cusp pattern was expressed.
During embryogenesis, HGF supports organogenesis and mor- phogenesis of various organs including liver, kidney, lung, gut, mammary gland and skeletal system (Matsumoto and Nakamura, 1996a, b). HGF appears also to be involved in tooth morphogen- esis. Tabata et al. (1996) documented the expression of HGF by dental mesenchyme from early cap to mid bell-stage of tooth development, and the expression of c-Met, the cognate receptor, by dental epithelial cells from cap to advanced bell-stage. These authors also analyzed the effects of HGF translation arrest by means of anti-sense oligodeoxynucleotides, and suggested that the imbalance between the proliferation activities of the IDE and dental mesenchyme caused by HGF translation arrest could lead to abnormal tooth morphogenesis. Abnormal tooth structures in
The main features of tooth morphogenesis have been conserved throughout evolution. All teeth form from surface oral epithelium and underlying neural crest-derived mesenchyme. Interactions between the tissues, mediated by conserved signaling pathways, control epithelial morphogenesis and cell differentiation (Tummers and Thesleff, 2009). In all vertebrates, the first sign of tooth development is the formation of an epithelial primary dental lamina. It can be recognized as a horseshoe-shaped thickening and as a localized band of gene expression in the embryonic oral cavity or pharynx that marks the future tooth rows (Fraser et al., 2009). In mammals, development of the primary dentition starts from epithelial placodes forming within the dental lamina. Knowledge concerning the role of placodes in the initiation of different types of teeth is still limited because they have been studied mainly in mice, which have only a single continuously growing incisor and three molars in each jaw quadrant (Fig. 1A).
Healing with surface resorption: is repair-related resorption (also described as surface resorption). It is a transient process involving small areas on the root surface following luxation and avulsion injuries. Typically, diagnosis can be made within 4 weeks after injury. This type of resorption is reversible. 12 Histologically it is characterized by localized areas along the root surface showing superficial resorption lacunae repaired by new cementum. In case of deeper resorption cavities, healing occurs, but without restoration of original outline of root. Radiographically, due to small size surface resorptions are usually not disclosed. Clinically, tooth is in normal position and normal percussion tone can be elicited.
Multiciliated cells (MCCs) possess multiple motile cilia and are distributed throughout the vertebrate body, performing important physiological functions by regulating fluid movement in the intercellular space. Neither their function during organ development nor the molecular mechanisms underlying multiciliogenesis are well understood. Although dysregulation of members of the miR-34 family plays a key role in the progression of various cancers, the physiological function of miR-34b, especially in regulating organ formation, is largely unknown. Here, we demonstrate that miR-34b expression is enriched in kidney MCCs and the olfactory placode in zebrafish. Inhibiting miR-34b function using morpholino antisense oligonucleotides disrupted kidney proximal tubule convolution and the proper distribution of distal transporting cells and MCCs. Microarray analysis of gene expression, cilia immunostaining and a fluid flow assay revealed that miR-34b is functionally required for the multiciliogenesis of MCCs in the kidney and olfactory placode. We hypothesize that miR-34b regulates kidney morphogenesis by controlling the movement and distribution of kidney MCCs and fluid flow. We found that cmyb was genetically downstream of miR-34b and acted as a key regulator of multiciliogenesis. Elevated expression of cmyb blocked membrane docking of centrioles, whereas loss of cmyb impaired centriole multiplication, both of which resulted in defects in the formation of ciliary bundles. Thus, miR-34b serves as a guardian to maintain the proper level of cmyb expression. In summary, our studies have uncovered an essential role for miR-34b-Cmyb signaling during multiciliogenesis and kidney morphogenesis.
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Increased dental anxiety associated with stimuli or physical sensations has been reported in people undergoing dental procedures such as “feeling the drill in the mouth” 6. A higher number of decayed tooth surfaces, tooth decay and missing teeth along with a lower number of tooth llings or functional teeth are more commonly seen in people with high dental fear compared to those with low dental fear. Interestingly, a study found no di erences in caries
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along the dorso-ventral axis. Second, the cells of the lateral epidermis elongate coordinately starting from the most dorsal and proceeding towards the most ventral ones in a morphogenetic wave. Coupled with this dorsalward movement, the anterior/poste- rior (A/P) axis stretches along the dorsal edge. These two move- ments result in the dorsalmost cells of the epidermis forming two straight lines (Martinez Arias, 1993; Ring and Martinez Arias, 1993). Finally, the epidermal layers meet at the dorsal midline, the dorsalmost cells lose their polarity, cell stretching stops and the epithelial sheet seals the gap to form a continuous epidermis. We could say, by analogy, that epidermal morphogenesis reaches "entelechia" and epidermal cells initiate their final differentiation on completion of dorsal closure.
Teeth maintain the integral balance between structure, function, and aesthetics. Loss of anterior tooth not only poses a social stigma for patients but also an additional challenge for the dentist as all patients seek immediate replacement, which in most of the cases is not practical and easily affordable. f adjacent teeth or are too costly in the form of immediate implants. Natural tooth pontic is less time consuming, easily fabricated, with a predictable outcome and can serve as an excellent interim restoration. It also concentrates on maintaining aesthetics and the This paper describes report of four cases in which immediate replacement of anterior tooth is done using a fibre composite resin with natural tooth serving as pontic.
Enamel is resistant to abrasion, and both the thickness and microstructure of enamel have evolved to prolong the life of a tooth. Nevertheless, tooth wear causes a gradual loss of crown morphology and eventually the loss of the tooth. When teeth are lost at a faster rate than the life span of an animal, solutions to preserve dental function have evolved. The prevalent solution is tooth replacement, in which a worn out or lost tooth is replaced with a new one (Fig. 4) that develops from the so-called successional dental lamina at the lingual side of the preceding tooth. Continuous replacement of teeth throughout the life span of an individual is likely to be basal for all vertebrates and is found from fish to reptiles. Mammals differ from other vertebrates in that they have a limited capacity for tooth renewal, and the majority of extant mammals replace teeth maximally once. The so-called diphyodont dentition – that is, having deciduous (first set, ‘milk teeth’) and then permanent incisors, canines and premolars – is found in humans. Almost 50% of orders have species that are not fully diphyodont, and many taxa, such as muroid rodents, bats, shrews and the striped skunk, do not replace any of their teeth; hence, they are monophyodont (van Nievelt and Smith, 2005). The fossil record of early mammals shows a gradual reduction in tooth replacement, usually attributed to the evolution of exact occlusion, which in turn evolved with an increase in dental complexity (Kielan-Jaworowska et al., 2004).
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The immature polycarp of Gamipa Americana (family Rubiaceae) is used for tooth extraction by placing the pulp of the plant onto the aching tooth, where it was left in place for several weeks causing disintegration of the tooth which is then removed in pieces, with little or no trauma . The stem-sap of Stigmaphyllon species (family Malpighiaceae) is placed on the carious tooth for about four hours followed by repeated applications throughout the day. After one week, the tooth can be removed without bleeding or pain . In Guatemala, boiled tree bark, herbs and camphor are used for the treatment of tooth and head pain . Daceryodes excelsa is thought to be the herb widely used to loosen teeth prior to extraction and its resin alleviates tooth- ache and loosens the roots of a dead tooth [33,34].
proposed, based on the above described analyses of the four evaluation systems. In a modular evaluation system, the following modules should be included: 1. A screen- ing module (both for epidemiological studies and for screening individual patients in the clinic) (Table 6); and 2. A module for diagnosing or monitoring individual pa- tients, for which both occlusal/incisal and non-occlusal/ non-incisal (finer grained) evaluation systems are needed (Table 7). Regarding the management of an individual patient, we think that during every recall appointment, assessment of tooth wear is a necessity. Because a lack of time can be a factor, the screening module is suitable. When the health care provider want to monitor the pro- gress of the tooth wear, the finer grained assessment can be performed during the recall sessions. Also, when a treatment plan for an individual patient is needed, one can assess the tooth wear in detail. One must realize that by the proposed modular evaluation system only quanti- fication is performed and no qualification is done. Concerning the screening module, the proposal is a 4- point ordinal scale as shown in Table 6. One can discuss about the cluster of teeth, as well as about the surfaces. One can assess only some key elements, per sextant, or all elements. One can assess only occlusal/incisal or also non-occlusal/non-incisal. Until agreement is reached, every individual researcher and/or dental clinician can make his/her own decision, based on the specific goal of the assessment. Concerning the diagnosing/monitoring module, the proposals are a 6-point ordinal scale for the occlusal/incisal surfaces, and a 5-point ordinal scale for the non-occlusal/non-incisal surfaces. These ordinal scales are based on the descriptions of the four analyzed tooth wear evaluation systems [5–8], and on the tooth wear evaluation systems as described by Lobbezoo and Naeije  and Wetselaar and coworkers . The modular evaluation system consists of three different ordinal scales. The descriptions for these three scales are similar for scores 0 and 1. For score 2, a different description exists; in the screening module the distinc- tion in clinical crown height is ≤1/2, while in the finer
The development of cranial primordia involves fundamental processes characterized by growth, morphogenesis, cell differen- tiation and pattern formation. Interactions between extracellular matrix (ECM) components, growth factors and embryonic tissues induce cell differentiation pathways and inductive events. During skull development, osteogenetic events are characterized by con- tinuous deposition of osteoid matrix and by resorption of the calcified bone matrix due to the changing curvature of the bones during development (Sullivan, 1986). The most severe anomalies of the calvarium, such as Crouzon and Apert syndromes, are characterized by premature fusion of skull sutures due to altered osteogenic processes at the time of calvarian development. It is possible that persistence and premature ossification of fetal su- tures initiate synostosis before the sutures become fully devel- oped. Biochemical and molecular aspects of craniofacial develop- ment, such as the biological regulation of normal or premature cranial suture fusion, are still largely unknown. In this review we
Pax Gene (Paired homeobox gene): This paired homeobox gene is a nine member family and plays a key role during embryogenesis and the significant contribution of this multifaceted gene was unveiled during its expression in some stem cells and mature cells of adult. It also functions as transcription factor present in mesenchyme. Zhao M et al., investigated the presence of Pax in dental mesenchyme and during arrest of tooth development . Bhatt S et al., has studied upon the anchor laid by this special gene in governing the signals needed for neural crest differentiation and further maturation . Paixao-Cortes VR et al., extensively examined the potential and presence in various processes and its structure . Several studies by authors investigated the pivotal axis laid down by this gene in tooth formation and thus agenesis was given supreme importance [48-50] [Table/Fig-7].
The main purpose of the work reported here was to re examine the behavior of the TCA cycle enzymes during the development of B. emersonii in synchronous cultures. It was hoped that such a study might offer clues to the biochemical mechanisms underlying morphogenesis in this mold. In some respects, our results contrast with previous v/ork and the assumptions derived therefrom (Cantino, 19ol and 1966). Before considering the results of the
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