Early development of the lower deciduous dentition and oral vestibule in human embryos

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1 Eur J Oral Sci 2007; 115: Printed in Singapore. ll rights reserved Early development of the lower deciduous dentition and oral vestibule in human embryos Hovorakova M, Lesot H, Vonesch J-L, Peterka M, Peterkova R. Early development of the lower deciduous dentition and oral vestibule in human embryos. Eur J Oral Sci 2007; 115: Ó 2007 The uthors. Journal compilation Ó 2007 Eur J Oral Sci The aim of this work was to investigate the early development of the deciduous dentition and oral vestibule in the human embryonic lower jaw. Histological sections and three-dimensional reconstructions from prenatal weeks 6 9 were used. continuous anlage for the oral vestibule did not exist in the mandible. In contrast to the upper jaw, where we previously observed that the dental and vestibular epithelia developed separately, two dento-vestibular bulges differentiated in the incisor region of the mandible. The lingual parts of each bulge were found to give rise to the respective central and lateral incisors, whereas the labial parts differentiated into the vestibular epithelium. In the canine and molar areas, the dental and vestibular epithelia originated separately. Later, the segments of the vestibular epithelium fused into the labial vestibular ridge, giving rise to the lower oral vestibule in the lip region. In the cheek region, the oral vestibule was found to originate in the mucosal inflection between the developing jaw and the cheek. similar heterogenous developmental base for the oral vestibule was also observed in the upper jaw. There is thus no general scheme for the early development of the dental and vestibular epithelia that applies to both the upper and lower jaws, and to both their anterior and posterior regions. Ó 2007 The uthors. Journal compilation Ó 2007 Eur J Oral Sci European Journal of Oral Sciences Maria Hovorakova 1, Herve Lesot 2,3, Jean-Luc Vonesch 4, Miroslav Peterka 1, Renata Peterkova 1 1 Department of Teratology, Institute of Experimental Medicine, cademy of Sciences CR, Prague, Czech Republic; 2 UMR INSERM 595, Strasbourg, France; 3 Universite Louis Pasteur, Faculte de Chirurgie Dentaire, Strasbourg, France; 4 Imaging Center Technology Platform, Institut de Genetique et de iologie Moleculaire et Cellulaire, Illkirch, France R. Peterkova, Department of Teratology, Institute of Experimental Medicine, cademy of Sciences CR, Videnska 1083, Prague 4, Czech Republic Telefax: repete@biomed.cas.cz Key words: deciduous tooth; dental epithelium; development; lower jaw; oral vestibule ccepted for publication May 2007 Tooth development in humans passes through the classical stages of odontogenesis: epithelial thickening; dental lamina; tooth bud; cap; and bell. Different authors have reported the first morphological signs of odontogenesis in human embryos from embryonic day (ED) 28 (1) to ED (2). It is generally accepted that the upper and lower deciduous teeth develop from the respective horseshoe-shaped dental lamina (3, 4). Textbooks on human embryology present another horseshoeshaped epithelial structure that runs parallel and externally (labial or buccal) to the dental lamina in embryonic jaws (Fig. 1). This is a vestibular lamina (also named the Ôlip-furrow bandõ or Ôlabio-gingival ridgeõ), which develops between the dental lamina and the future lips and cheeks (5 8). The vestibular lamina is considered to be the developmental base of the oral vestibule, which is the free space between the alveolar portion of the jaws, including the teeth, and the lips or cheeks (6). Some textbooks do not mention the development of the oral vestibule at all (4, 9). Many authors have discussed the developmental relationship between the dental and vestibular laminae in humans, suggesting their independent development as two parallel epithelial anlagen (5, 6, 10), or that they arise from a common epithelial thickening (2, 7, 11), or that these laminae are subdivisions of a common thickened epithelial base in the anterior region and develop separately in the posterior region (12, 13). However, three-dimensional (3D) imaging has documented that the formation of the oral vestibule is much more complex in the human upper embryonic jaw (14). No continuous horseshoe-shaped vestibular lamina exists. Instead, the upper vestibular epithelium includes a series of epithelial bulges and ridges (Fig. 1). The dental and vestibular epithelia are regionalized in parallel along the mesio-distal axis. They reiteratively fuse together behind the developing upper deciduous canine, first molar, and second molar (14). The aim of this study was to investigate the early morphogenesis and developmental relationships of the dental and vestibular epithelia in the human lower jaw, and to compare them with what has previously been observed in the upper jaw (14). Material and methods Embryos and fetuses The development of the dental epithelium was examined in a collection of serial histological sections held by the Department of Teratology, IEM S CR, in Prague. The collection comprises 53 series of frontal and 7 series of sagittal histological sections of the heads of normal human embryos (from artificially aborted embryos of unwanted pregnancies) compiled from the 1960s to the 1980s.

2 Human lower dentition and oral vestibule 281 Fig. 1. Schemes of the spatial relationship between the dental and vestibular epithelium in human embryos. Yellow, dental epithelium; orange, base of the oral vestibule. The remaining vestibular epithelium is green. () ccording to the generally accepted concept, the oral vestibule arises from a vestibular lamina (VL), which is a continuous structure running externally and parallel to the dental lamina (DL). () Data on the upper jaw (14) have shown epithelial bulges that initially emerge externally to the dental epithelium in the lip region. They fuse, being transformed into the canine vestibular ridge (CVR) in the posterior direction. The CVR fuses with the dental mound behind the deciduous canine primordium (c). In the cheek region, the vestibular epithelium forms the molar vestibular ridge (MVR) and the cheek-furrow ridge (the CFR is the epithelium lining the mucosal inflection between the alveolus with teeth and cheeks). The MVR splits posteriorly into the medial (MMVR) and lateral (LMVR) branches. The fornix of the oral vestibule originates from the bulges and the CVR in the lip region and from the CFR in the cheek area (14). C, accessory epithelial cap; m 1 and m 2, the upper first and second deciduous molars, respectively. (C) Present data on the lower jaw. The level of the mouth corner (MC) is labeled. Different vestibular structures are shown: the area of irregularly thickened vestibular epithelium (ITVE), the labial vestibular ridge (LVR), and the mandibular cheek furrow ridge (dcfr). The deciduous lower tooth primordia are labeled: m 1, first molar; m 2, second molar. C Table 1 The specimens used for three-dimensional reconstructions ranked according to the stage of tooth development. Specimen number Fixation ge Secondary palate formation* Developmental horizon (15) Carnegie stage (16) Reconstructed lower jaw quadrant HU1 ouin-hollande ED XX Right HU3 Formol 10% ED XXI 17 Right HU9 ouin-hollande ED XXII 18 Left HU10 Formol 10% ED XXII 18 Right HU5 ouin-hollande ED /+ XXII 18 Left HU11 ouin-hollande ED /+ XXII 18 Right HU6 ouin-hollande ED /+ XXII 18 Right HU7 ouin-hollande Week 8 + The upper and lower Right eyelids are not fused (2) HU8 ouin-hollande Week 9 + The upper and lower eyelids are fused (2) Left ED, embryonic day *( ) Horizontalization of palatal shelves has not yet started; ( /+) horizontalization started, one of the palatal shelves was horizontalized or both palatal shelves were horizontalized but not yet fused; (+) palatal shelves were fused. Only half of the embryonic head was available in which the palatal shelf was not yet horizontalized (it was not possible to determine the position of the second palatal shelf). Determination of the embryonic stage s homogenous data allowing stage determination were not available for all specimens, the staging of embryos (younger than prenatal week 8) was checked and expressed on the basis of Ôdevelopmental horizonsõ (15). The staging of fetuses (prenatal week 8 and older) was based on the morphological criteria proposed by Moore &Persaud (4). s a main criterion of staging, we used the development of the eye on frontal sections in all embryos and fetuses investigated. The staging was also correlated with the staging according to the Carnegie Collection (16). In addition, the staging based on the classical methods was specified by the stage of tooth development. The Ôtooth ageõ allowed further ranking of a group of the embryos that exhibited the same stage determined by classical methods (see the alignment of embryos at ED in Table 1), as has been similarly documented in the mouse (17). Histology fter fixation in ouin Hollande fluid or in 10% formol, the heads were embedded in paraffin, cut in serial frontal sections (10 lm thickness), and stained by hematoxylin &

3 282 Hovorakova et al. eosin, alcian blue hematoxylin & eosin, or by a Periodic cid Schiff method. The early stages of tooth development (epithelial thickening, dental lamina, tooth bud) were identified according to criteria reported by Peterkova et al. (18). Computer-aided 3D reconstructions Three-dimensional reconstructions of the dental and adjacent oral epithelium of the lower jaw quadrant were performed in a representative sample of nine human embryos (Table 1). This sample showed a longitudinal adjustment of the successive steps of tooth development. In each of the embryos, the right or left jaw quadrant was randomly selected for 3D reconstruction. Contours of the dental and adjacent oral epithelium were drawn (magnification , depending on the size of the specimen) at 10-lm intervals from each of the serial histological sections using a Leica DML (Leica Microsystems, Wetzlar, Germany) or a Jenaval (Carl Zeiss, Jena, Germany) microscope equipped with a drawing chamber. The superimposition of the drawings was performed by the Ôbest fitõ method (19) with respect to the middle line and horizontal level for correct spatial positioning of the reconstructed structures. The digitalization of the serial drawings and the correlation of successive images have previously been described (20). Three-dimensional images were generated using a volume-rendering program (Sun Voxel Sun Microsystems, Santa Clara, C, US). In addition to different views on the 3D reconstructions, we also performed sagittal sections through the 3D reconstructions for complementary visualization of the relationships between the dental and vestibular epithelia. Results Morphology of the dental epithelium In a jaw quadrant at ED 40 42, two fields of thickened epithelium were present along the mesio-distal axis (Fig. 2). These thickenings were situated in an end-toend orientation and separated by a deep notch (Fig. 2). The adjacent ends showed a bulge shape corresponding to the regions of the deciduous lower lateral incisor (i 2 ) and canine (c), respectively. nother bulge was observed in the region of the deciduous lower central incisor (i 1 ) (Fig. 2). The two bulges in the incisor region comprised the prospective dental and vestibular epithelia (dento-vestibular bulges). The lingual parts of these bulges protruded (prospective buds of deciduous i 1 and i 2 ), whereas the labial parts C Fig. 2. Computer-aided three-dimensional reconstructions of the epithelium on the oral surface of the lower jaw in HU1 at embryonic days (ED) (), in HU3 at ED (), and in HU10 at ED (C) at different stages of development (see Table 1) and their schematic interpretation. The deciduous lower tooth primordia are labeled: c, canine; i 1, central incisor; i 2, lateral incisor; and m 1, first molar. Different vestibular structures are shown: the labial vestibular ridge (LVR), the irregularly thickened vestibular epithelium (ITVE), and the epithelium lining the inflection of the forming lower vestibule adjacent to the cheek region of the mandible (dcfr). The position of the mouth corner (MC) and ductus parotideus (DP) is indicated. The midline is shaded. The levels labeled h j indicate the positions of frontal histological sections shown in Fig. 4H J, respectively.

4 Human lower dentition and oral vestibule 283 remained low (prospective vestibular epithelium). The bulge in the canine region corresponded to the primordium of c. From the canine region, a thickening of the dental epithelium extended in the distal direction (Fig. 2), where the deciduous lower first molar (m 1 ) showed the bud stage. t ED 42 44, the buds of i 1 and i 2 differentiated from the lingual parts of the corresponding bulge. During further development, the labial parts of the two dentovestibular bulges in the incisor region gave rise to the vestibular epithelium. Further posteriorly along the course of the mandible, the dental epithelium formed a mound with swellings at the places of c and m 1 (Fig. 2). s tooth swellings, as well as the mound, showed a bud shape on frontal sections, it was not yet possible to delimitate tooth primordia at a bud stage. However, tooth primordia started to be distinct in developmentally more advanced embryos at ED (HU10 and older embryos; see Table 1, Fig. 2C), after the teeth reached a cap stage, whereas the mound epithelium in interdental spaces retained a bud-shape on frontal sections (Fig. 2C). During prenatal wk 8 the situation was similar to that at ED However, the tooth caps were more differentiated (Figs 3 and 4). In the oldest examined fetus (HU8), i 1,i 2, c, and m 1 reached the bell stage of tooth development, and the cap of the deciduous second molar (m 2 ) became distinct (Fig. 3). t all stages, the dental epithelium divided into two parts behind the most distal developing tooth. The medial band disappeared after a short distance, whereas the lateral band continued in a disto-lateral direction (e.g. Figs 2 and 3). Morphology of the vestibular epithelium The vestibular epithelium did not arise as a continuous vestibular lamina. While the bulges in the incisor area were formed by the dento-vestibular epithelium (ED 40 44), the dental and vestibular epithelia developed separately in the canine molar area. In the incisor area, the labial parts of the epithelial bulges progressively separated from i 1 and i 2 as the vestibular epithelium. In the canine and molar regions, the band of thickened vestibular epithelium was present externally to the dental epithelium at ED (Fig. 2). In the cheek region, the area of the irregularly thickened vestibular epithelium (ITVE) differentiated from ED (Figs 2, 3 and 4E G). Fig. 3. Computer-aided three-dimensional reconstructions of the epithelium on the oral surface of the lower jaw in HU7 at prenatal wk 8 () and HU8 at prenatal wk 9 () at different stages of development (see Table 1) and their schematic interpretation. In () only the distal part of the long dental arch could be reconstructed because of the technical limits of the camera. The deciduous tooth primordia are labeled: c, canine; i 1, central incisor; i 2, lateral incisor; m 1, first molar; and m 2, second molar. Different vestibular structures are shown: the labial vestibular ridge (LVR), the irregularly thickened vestibular epithelium (ITVE) and the epithelium lining the inflection of the forming lower vestibule (dcfr). The position of the mouth corner (MC) and ductus parotideus (DP) is indicated. The midline is shaded. The levels labeled a g indicate the positions of frontal histological sections shown in Fig. 4 G, respectively.

5 284 Hovorakova et al. C E H I J t ED 44 46, the vestibular and dental epithelia transiently fused in the canine region (Fig. 2C). Later, the vestibular epithelium again separated from the canine primordium and fused posteriorly with the ITVE and anteriorly with the vestibular epithelium in the incisor region (Fig. 3). The fused vestibular epithelium in the incisor and canine regions and the medial part of the ITVE gave rise to the labial vestibular ridge (LVR) (Figs 2C, 3 and 4 E). In week 8, the LVR extended as far as to the m 1 level. The LVR closely approached the dental mound anteriorly to m 1 (Fig. 3), but we did not observe a fusion. t ED 40 42, an epithelial ridge differentiated in the most lateral part of the cheek region of the mandible. This mandibular cheek furrow ridge (dcfr) remained located laterally to the ITVE at all subsequent stages under observation (Figs 2 and 3). The dcfr epithelium lined the mucosal inflection (the prospective lower part of the oral vestibule) between the developing alveolus and the cheeks. Discussion Tooth development F D Fig. 4. Frontal histological sections showing the lower dental and vestibular epithelia at prenatal wk 8 ( G) and at embryonic days (ED) (H J). The images shown in panels J were taken at the levels a j indicated in Figs 3 and 2C. The deciduous tooth primordia are labeled: c, canine; i 1, central incisor; i 2, lateral incisor; and m 1, first molar. The vestibular structures are shown: the labial vestibular ridge (LVR) and the irregularly thickened vestibular epithelium (ITVE). The branching (not visible on views on three-dimensional models in Figs 3 and 2C) at the posterior end of the dental epithelium is shown at prenatal wk 8 (E G) and at ED (H J). lack arrowheads point to the dental epithelium. ar, 100 lm. On histological sections, the deciduous teeth passed through the typical stages of tooth development: the G thickening, lamina, bud, cap, and bell. However, the 3D reconstructions showed that deciduous tooth buds do not have the form of isolated buds protruding from a surrounding epithelium. t the so-called bud stage, the dental epithelium formed a dental mound, which showed a bud shape on frontal sections along the antero-posterior course of the mandible. t the places of developing canine and m 1, only swellings were apparent on the mound in 3D reconstructions, corresponding to the increased size of the bud-shaped epithelium on frontal sections. This is why it was not possible to determine the exact limits of the deciduous tooth primordia before the cap stage (Figs 2 and 3). Such morphology of the tooth primordia at the bud stage has also been documented in the human upper jaw (14) and during mouse molar development (18, 21). It has been reported that the epithelial anlage of the deciduous dentition originates at the same time in the upper and lower jaws (22). However, a comparison of our previous (14) and present data supports the suggestion that the development of the upper teeth lags behind the development of the lower dentition (5, 10). This lag has been related to the complex development in the upper portion of the face (brain, sense organs, nasal cavity), which is also in progress at the time of tooth development (5). The unbalanced development of the upper and lower dentitions can also be explained by the fact that the maxillary and mandibular branches of the first branchial arch grow unequally in time and size (23). method of reciprocal cell transplantations between maxillary and mandibular arch ectomesenchymal cells revealed intrinsic differences between these populations of cranial neural crest-derived cells in the mouse, which respond differently to epithelial signals. These differences have been related to the different origins of the neural crest cells that populate these components of the first branchial arch (24). In the axolotl, direct cell lineage analysis in vivo has shown that there are two independent condensations of neural crest cells flowing into the maxillary and mandibular outgrowths, respectively (25). In human functional dentition, the deciduous teeth are located next to one another and the interdental spaces are negligible. However, significant spaces separate individual tooth germs during development (Figs 2 and 3). This means that the growth rate will have to be higher in the tooth germs than in the interdental spaces until the tooth reaches the bell stage. Generally, the interdental spaces between the developing anterior teeth (incisors) are shorter in comparison to the interdental spaces in the distal regions (canine and molars) in both upper and lower jaws (26, 27). The most significant interdental space was present between the canine and the first molar in both the upper (14) and lower (Figs 2 and 3) jaws. This can be explained by the reduction in tooth number during human evolution. The basic mammalian tooth formula comprises 3 incisors, 1 canine, 4 premolars, and 3 molars (28). The human deciduous first and second molars have been homologized with the respective deciduous third and

6 Human lower dentition and oral vestibule 285 fourth premolars from the basic mammalian dentition (29). The missing first and second premolars might explain the presence of a significant interdental space between the canine and the first deciduous molar (¼ third deciduous premolar) in the human embryonic dental arch. The vestibular epithelium and the prospective vestibule of the mouth There was always a protrusion of the vestibular epithelium externally to the dental epithelium on histological sections (Fig. 4). Without correlation with the corresponding 3D views, this protrusion could be considered as a component of a continuous horseshoe-shaped vestibular lamina, giving rise to the prospective oral vestibule (Fig. 1). The concept of the development of the oral vestibule from a continuous vestibular lamina has been presented by many authors (1,5) and is still maintained in embryological textbooks (6 8). However, the present 3D reconstructions did not show any continuous vestibular lamina in the lower jaw (Figs 2 and 3). In its place, there were several discontinuous epithelial structures (Fig. 1C) as already observed in the upper jaw (14) (Fig. 1). The vestibular epithelium adjacent to the incisor primordia was segmented in parallel to individual teeth in both the upper (14) and lower jaws (Fig. 1). However, there was an apparent difference: in the upper incisor region, the segments of the dental and vestibular epithelia arise separately (14), whereas in the lower incisor region, there were two segments (bulges), each comprising precursors of the prospective incisor and its adjacent vestibule (Figs 1 and 5). In the canine and cheek region of both the upper (14) and lower jaws, the dental and vestibular epithelia arose independently (Figs 1, 2 and 5). The lower oral vestibule had different developmental origins in the lip and cheek regions (Fig. 1C). In the lip region, it developed from the labial vestibular ridge, which presumably corresponds to the Ôlip-furrow-bandÕ of, for example Schour (5), or with the Ôlabio-gingival sheetõ of olk (11). However, in the cheek region of the mandible (located behind the level of the mouth corner), the oral vestibule originated from the epithelial ridge that lines the inflection between the cheeks and the prospective alveolus (Fig. 1C). The distinct origins of the fornix of the oral vestibule in the lip and cheek regions have also been reported in the human upper jaw (14) (Fig. 1), in mice (30), and in sheep (31). The developmental relationship between the dentition (dental lamina) and the oral vestibule (vestibular lamina) has not been completely explained in the literature. It has been stated that these structures: (i) evolve separately (5, 6, 10); (ii) have a common origin (2, 7, 11); or (iii) are subdivisions of a common thickened epithelial base anteriorly, whereas they develop as two separate epithelial structures in the posterior regions of the jaw (12, 13). C D Fig. 5. Comparison of the upper and lower dental (DE) and vestibular (VE) epithelia on three-dimensional (3D) reconstructions. The DE and VE of the upper (, ) and lower (C, D) jaws of the embryo HU2 [embryonic days (ED) 42 44] are presented as an aerial view on the 3D reconstruction (, C) and on a sagittal section through the 3D reconstruction (, D). In the upper incisor region, DE and VE differentiate apart from each other, being separated by a groove indicated by a blue arrow (, ). However, in the lower jaw, one bulge formed by the dento-vestibular epithelium (DVE) is present in each of the central and lateral incisor regions (C, D). t later stages, the lingual parts of the two bulges give rise to i 1 and i 2, respectively. The labial parts differentiate into the vestibular epithelium. The midline is shaded.

7 286 Hovorakova et al. These different concepts might result from observations performed by different authors on different jaws (upper or lower) and jaw regions (lip or cheek region) in embryos at different developmental stages. Our data clearly show that each of these concepts correctly reflects only one particular situation, depending on the region and the time of observation (Figs 1 and 5). In the upper jaw, there are two separate epithelial thickenings: the inner dental and outer vestibular epithelia (14). This observation corresponds with the first concept mentioned above, proposing the independent development of the dentition and oral vestibule (5, 6, 10). Nevertheless, the parallel segmentation of the dental and vestibular epithelia in the upper jaw suggests their close developmental relationship (14). The situation was completely different in the lower jaw (Fig. 1C) compared with the upper jaw (Fig. 1). The dental and vestibular epithelia developed from a common dento-vestibular bulge, which was present in both the central and lateral incisor regions (Figs 2 and 5). This situation fits with the second concept that suggests a common origin of the dentition and the oral vestibule (2, 7, 11). In the posterior (canine and cheek) region of the lower jaw, the dental and vestibular epithelia originated separately (in accordance with the first concept above) (Figs 1C and 2). So, the present data on the lower jaw correspond with the third above-mentioned concept regarding the common origin of the dentition and the oral vestibule in the anterior region and their separate origin in the posterior region of the jaw (12, 13). The dental and vestibular epithelia develop separately on the fused facial processes forming the upper jaw arch (14). However, if traced to earlier stages, they might also have a common origin in the epithelial plate that has been observed on each of not-yet merged facial outgrowths in human embryos (1, 32). If sufficiently young mouse embryos are investigated, a similar common developmental origin can be traced out, giving rise not only to teeth and oral vestibule, but even to the palatal ridges. ased on this ontogenetic relationship, the palatal ridges and the oral vestibule have been presented as odontogenous structures from a phylogenetic aspect (30). The latent odontogenous potential of the vestibular epithelium can be further supported by the integration of the vestibular epithelium into the dental lamina in the mouse (30) and in humans (14). It has been suggested that the structures of the vestibular epithelium in mammals might have an evolutionary relationship to the earliest generations of teeth in reptiles (33). The complex development of the oral vestibule might help to explain some of the pathologies located externally to the functional dentition. cknowledgements We thank Prof. J. Slipka (Institute Histol. Embryol., Medical Fac., Charles University, Pilsen, CR) for providing a part of human embryological material and Mr J. Dutt for critical reading of the manuscript. This study was supported by the Grant gency of the Czech Republic (304/05/ 2665), Ministry of Education, Youth, and Sports of the Czech Republic (project COST ) and by the cademy of Sciences of the Czech Republic (project V0Z ). References 1. Nery E, Kraus S, Croup M. Timing and topography of early human tooth development. rch Oral iol 1970; 15: Röse C. U ber die Entwicklung der Za hne des Menschen. rch Mikr nat 1891; 38: Tuchmann-Duplessis H, Haegel P. Illustrated human embryology, Vol. II. Organogenesis. London: Chapman & Hall, Moore KL, Persaud TVN. The developing human, 5th edn. Philadelphia: W.. Saunders Co., Schour I. 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