Evolutionary Implications of the Occurrence of Two Vestigial Tooth Germs During Early Odontogenesis in the Mouse Lower Jaw

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1 Connective Tissue Research, 43: , 2002 Copyright c 2002 Taylor and Francis /02 $ DOI: / Evolutionary Implications of the Occurrence of Two Vestigial Tooth Germs During Early Odontogenesis in the Mouse Lower Jaw Laurent Viriot, 1 Renata Peterková, 2 Miroslav Peterka, 2 and Hervé Lesot 3 1 CNRS UMR 6046, Laboratoire de Géobiologie Biochronologie et Paléontologie Humaine, FacultéSFA, Université de Poitiers, 40 avenue du Recteur Pineau, Poitiers Cedex, France 2 Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, Prague 4, Czech Republic 3 INSERM U424, FacultédeMédecine, 11 rue Humann, Strasbourg Cedex, France The study of closely-spaced developmental stages reveals the occurrence of three distinct dental segments during early odontogenesis in the ICR mouse lower jaw: the mesial (MS), the second rudimentary (R2), and the molar segments. At embryonic day (ED) 12.5, the MS displays an accessory bud, which regresses rapidly and disappears at ED The R2 segment reaches a wide bud stage at ED 13.5 and then merges with the mesial end of the emerging first lower molar (M 1 ) cap before ED The MS and R2 segments never develop into functional teeth and are classified as vestigial tooth germs. Depending on their developmental chronology and on the position they occupy along the prospective mandibular tooth row, MS and R2 segments are putatively assigned to primordia of a third (dp 3 ) and fourth (dp 4 ) lower deciduous premolar, respectively. Evolutionary implications of these developmental data are discussed. Keywords Mouse, Tooth Development, Vestigial Teeth, Dental Formula, Evolution. INTRODUCTION Teeth are the hardest tissues in mammals and, as such, are more readily fossilized than other organs. A number of fossil taxa are known by isolated teeth only and occasionally by their dental formula. Hence, most taxonomic and evolutionary studies are based on comparisons of dental characters. Comparative dental anatomy involves the identification of homologies at different levels: the evaluation of tooth homology through the course of mammalian evolution is a first step, with a second one being the Received 19 June 2001; accepted 28 November Address correspondence to Laurent Viriot, Laboratoire de Géobiologie, Biochronologie et Paléontologie Humaine, CNRS UMR 6046, Faculté des Sciences Fondamentales et Appliquées, Université de Poitiers, 40, avenue du Recteur Pineau, Poitiers Cedex, France. Laurent.Viriot@univ-poitiers.fr evaluation of cusp homology in similar teeth. However, either the reduction of the dental formula or the complication of the occlusal pattern makes it difficult to identify homologies. Joint investigations involving paleontology and developmental biology have recently proved able to solve specific problems with evolutionary changes in tooth morphology and dental formulas (for reviews see refs. 1 3). Cases of marked reductions in the deciduous and permanent dental formulas are very common in rodents. Muroid rodents (e.g., rat, mouse, hamster, gerbil, and vole) develop only 16 functional teeth, while the presumed unreduced mammalian dental formula [4] implies that primitive eutherians were developing at least 72 functional teeth throughout their life. The mouse (Mus musculus) develops a functional dentition composed, in each quadrant, of one incisor and three molars separated by a diastema. Various data clearly indicate that this functional dentition does not reflect the situation during embryonic development [5, 6]. During early odontogenesis, dental primordia appear and progress in the maxillary diastemal region [7, 8], then regress and are eliminated by localized time-spaced apoptotic process [9, 10]. Other primordia also occur in the mandibular jugal region [11, 12]. A different but equally complex situation occurs in both mandibular and maxillary incisive regions [13, 14]. This article seeks to clarify tooth reduction during early odontogenesis in the mandibular jugal region of the mouse, taking into consideration morphological and histological data and focusing on evolutionary implications. MATERIALS AND METHODS Staging, Histology, and 3D Techniques Early tooth morphogenesis was investigated in ICR mouse embryos whose age was determined in embryonic days (ED) 129

2 130 L. VIRIOT ET AL. and specified by the wet body weight of specimens [15]. Females were mated overnight, and the midnight before the morning detection of the vaginal plug was taken as ED 0.0. Embryos were distributed by weight classes (wtc.) and fixed in Bouin Hollande fluid. Five micrometric frontal serial sections from paraffin embedded heads were stained with alcian blue hematoxylin eosin. The contours of the mandibular oral epithelium were drawn from serial histological sections. The digitization of the serial drawings, correlation of successive images, and three-dimensional (3D) reconstruction tools have been described previously [16]. The studied stages were: ED 12.5a, wtc mg; ED 12.5b, wtc mg; ED 12.5c, wtc mg; ED 13.0a, wtc mg; ED 13.0b, wtc mg; ED 13.5a, wtc mg; ED 13.5b, wtc mg; ED 14.0a, wtc mg; ED 14.0b, wtc mg; ED 15.0, wtc mg; ED 15.5, wtc mg; ED 16.0a, wtc mg; and ED 16.0b, wtc mg. DEVELOPMENT OF THE MS AND R2 SEGMENTS FROM ED 12.5 TO ED 16.0 Early Development of the Dental Epithelium Tooth germs in the prospective maxillary and mandibular jugal regions have been assigned to segmental odontogenic entities [3]. During early odontogenesis in the mouse lower jaw, studies of closely spaced developmental stages demonstrate the occurrence of three distinct dental segments aligned mesio-distally [12]: the mesial segment (MS), the second rudimentary (R2) segment, and the molar segment (Figures 1 3). 1. The MS displays a mesio-lingual accessory bud at ED 12.5a (Figure 1A). This accessory bud reaches a maximum size at ED 12.5b (Figure 1B), then regresses and disappears completely after ED 13.5b (Figure 1D). The remaining dental lamina of the MS elongates between ED 13.0 and 13.5a, then regresses and is transformed into an epithelial ridge. The strong apoptotic concentrations observed in the MS from ED 12.5b to ED 13.5 probably play an important role in the regression of this segment. Figure 2. Morphogenesis of the mandibular jugal region in the mouse embryo reconstructed in 3D (distal up, lingual left) and documented at (A) ED 14.0a and (B) ED From ED 14.0a, the R2 segment (star) is not distinguishable from the mesial end of the emerging M 1 cap (dot) because of the strong overlapping of these two entities. Bars: 100 µm. 2. The R2 segment grows and gradually constitutes the most conspicuous structure of the jugal odontogenic region at ED 13.0 (Figure 1, B and C). From ED 13.0a, an apoptotic concentration occurs near the oral surface of the R2 bud, then extends in the apical part of the bud during ED 13.5, and regresses significantly from ED The R2 segment forms a wide bud at ED 13.5 and is separated from the molar bud by a short constriction (Figure 1D). From ED 13.5 to ED 14.0, the R2 remains unchanged. It further merges with the mesial end of the emerging M1 cap and cannot be identified as a distinct structure after ED 14.0a (Figure 2, A and B). Figure 1. Morphogenesis of the mandibular jugal region in the mouse embryo reconstructed in three dimensions (3D) (distal up, lingual left) and documented at (A) ED 12.5b, (B) ED 13.0a, (C) ED 13.0b, and (D) ED 13.5a. Three distinct dental segments aligned mesio-distally occur during early odontogenesis: the mesial segment (MS) and its accessory bud (arrow), the second rudimentary (R2) segment (star), and the molar segment (dot). Bar: 100 µm. Figure 3. Chronology of development of the three dental segments observed in the mandibular jugal region of the mouse embryo from ED 12.0 to ED 16.0; L, lamina stage. The accessory bud of the MS progresses until ED 12.5b, then regresses and disappears completely by ED 13.5b. The R2 segment progresses from ED 12.5 until ED 13.5, then remains unchanged and merges with the mesial end of the emerging M 1 cap. The molar dental lamina increases from ED 12.5, reaches the bud stage at ED 13.5, the cap stage at ED 14.0b, and the early bell stage between ED 15.0 and ED 15.5.

3 3. The molar dental lamina increases in the distal extension of the R2 segment between ED 12.5 and ED M 1 reaches the bud stage at ED 13.5 (Figure 1D), the cap stage at ED 14.0b (Figure 2B), and the early bell stage between ED 15.5 and ED 16.0a (Figure 3). VESTIGIAL TEETH IN MOUSE 131 The R2 Segment Between ED 14.0 and ED 16.0 Contrary to the situation at ED 13.5 (Figure 1D), the constriction between the bud of the R2 segment and the more distal molar epithelium seems to vanish gradually as a consequence of the mesial growth of the M 1 cap at ED 14.0a (Figure 2A). Between ED 13.5 and ED 15.0 (Figure 2B), the size of the R2 segment does not change substantially in morphometric curves, whereas the central part of the M 1 grows larger [12]. This suggests that the apoptotic waves between ED 13.0 and ED 13.5 might be involved in a growth retardation of the R2 bud, which is developmentally more advanced than the distally located molar epithelium at ED However, a question remains outstanding: Will the R2 bud remain inactive during further development of the M 1 enamel organ or will it contribute to the development of the M 1 mesial cusps? EVOLUTIONARY IMPLICATIONS Eutherian Dental Formulas The mammalian dentition can be classically divided into three mandibular and maxillary regions, in which teeth differ significantly in morphological and functional aspects [17, 18]: a frontal region with sharp, prehensile teeth (incisors); a canine region with lacerating, conical teeth (canines); and a jugal region with grinding or cutting teeth (premolars and molars). Mammals are also diphyodont, meaning that they develop two generations of dentition (one deciduous and one permanent). Since the dentition is symmetrical about the sagittal plane in vertebrates, the dental formula needs to include only half the number of teeth. The primitive quantitative dental formulas of eutherians comprise a deciduous dentition with three incisors, one canine, and four premolars (3/3 1/1 4/4) replaced by the permanent dentition that includes three incisors, one canine, three premolars, and three molars (3/3 1/1 3/3 3/3) in each dental quadrant [4]. The three molars are usually classified as permanent teeth, even if many authors consider molars as unreplaced deciduous teeth (see discussion in ref. 1). As this article does not address this problem, we prefer to consider molars as permanent teeth. Aside from the quantitative dental formula, the qualitative dental formula (QDF) displays a great deal of supplementary information about homology between the dentition of different taxa [18]. Each tooth is symbolized by the initial of its category, and a number indicates its position in the eutherian unreduced deciduous (di 1-3 /di 1-3 dc/dc dp 1-4 /dp 1-4) and permanent (I 1-3 /I 1-3 C/C P 2-4 /P 2-4 M 1-3 /M 1-3) dental formulas (Figure 4A). In almost all eutherians, a successor for dp1 is normally absent [1, 4]. Rodents all develop reduced dental formulas, characterized by one pair of incisors in each jaw and a variable number of Figure 4. (A C) Qualitative dental formulas (QDF). (A) Eutherian unreduced QDF. The deciduous dentition (gray rectangles) includes 32 teeth (di 1-3 /di 1-3 dc/dc dp 1-4 /dp 1-4 ) whereas the permanent dentition (black rectangles) lacks P 1 (I 1-3 /I 1-3 C/C P 2-4 /P 2-4 M 1-3 /M 1-3 ) and comprises 40 teeth. (B) Highly reduced deciduous (di?2 /di?2 dp 3-4 /dp 4 ) and permanent (P 3-4 /P 4 M 1-3 /M 1-3 ) QDF in extant primitive rodents. A long diastema is present at the place of missing teeth. (C) Deciduous (di?2 /di?2 ) and permanent (M 1-3 /M 1-3 ) QDF of the modern mouse, which lacks lower and upper premolars. (D) Mandibular embryonic dental formula (EDF) of the ICR mouse. MS and R2 have been putatively assigned to vestigial tooth germs (gray circles) of dp 3 and dp 4, respectively. The dp 3 germ aborts at early bud stage, while the dp 4 bud merges (gray arrow) with the mesial part of the M 1 cap. PMx, premaxillary; Mx, maxillary; D, dentary. deciduous and permanent jugal teeth. Rodent upper and lower incisors have been demonstrated to be second deciduous incisors (see discussion in ref. 19). It has been documented, however, that the upper incisor in the mouse could be a composite structure integrating the connate development of five or six placodes, putatively corresponding to premaxillary teeth in mammalian ancestors [13]. A preliminary study has suggested that at least three components might be integrated during the lower incisor development in the mouse [20]. This unclear ontogenetic assessment of the rodent incisors to the second deciduous incisors in other mammals will be indicated here by a question mark (di?2 /di?2 ). As the incisors are ever-growing teeth in rodents and lagomorphs, they will never be replaced, but maintained throughout life. The functional dentition of rodents is therefore

4 132 L. VIRIOT ET AL. not monophyodont but composite, comprising both deciduous and permanent teeth. In each dental quadrant, two incisors, the canine, and a variable number of premolars are missing from the dentition of the extant primitive rodents (e.g., squirrel, marmot), whose deciduous and permanent QDF are di?2 /di?2 dp 3-4 /dp 4 and P 3-4 /P 4 M 1-3 /M 1-3 (Figure 4B). As a consequence, a long diastema is present. The mouse lacks lower deciduous or permanent premolars (deciduous and permanent QDF are di?2 /di?2 and M 1-3 /M 1-3), and so has an even longer diastema (Figure 4C). Putative Homologies of Vestigial Tooth Germs The MS and R2 segments never develop into independent functional teeth and so may be classified as vestigial tooth germs in the terminology of Moss-Salentijn [6]. These vestigial tooth germs appear before the M 1 enamel organ is distinct. On the basis of the chronology of development and the position of these vestigial tooth primordia along the prospective mandibular tooth row, we may hypothetically assign the MS to the primordium of the third lower deciduous premolar (dp 3 ), and the R2 segment to the primordium of the fourth lower deciduous premolar (dp 4 ). This hypothesis could be tested by further comparative embryological studies and by experimental approaches. Further development of these rudiments by inhibiting apoptosis could help to elucidate this problem. Likewise, independent development of these rudiments might be stimulated and their coalescence suppressed by modifying the budding activators/inhibitors interplay [3]. Evolutionary Importance of Vestigial Tooth Germs Vestigial tooth germs are embryonic characters, which fail to appear in the adult phenotype. They correspond to repetitive primordia of dental structures, which developed normally in ancestors [3]. Luckett [1, 19] emphasized the use of vestigial tooth germ homologies for studying evolutionary relationships among mammals. Moss-Salentijn [6, 21] and Luckett [1, 19] reported that vestigial tooth germs abort at various stages during odontogenesis, with some developing until late stages (mineralization), whereas others abort early. The latter case applies to the MS (putative dp 3 ) in the mouse, which begins to regress at the early bud stage. The outcome of the R2 (putative dp 4 ) regression is difficult to evaluate because of its merging with the M 1. Our results clearly demonstrate that the two classical dental formulas for the deciduous and permanent teeth are not sufficient to depict all the events that occur during odontogenesis in the mouse. We therefore propose to consider also an embryonic dental formula (EDF), indicative of the true odontogenic potential of a species including the vestigial tooth germs. The functional teeth of the qualitative dental formula will be supplemented by the vestigial teeth (in brackets) to indicate that their primordia occur but never lead to functional teeth. The EDF would be a new tool to identify affinities and to understand the process involved in dental reduction in the course of mammalian evolution. As an example, and taking into account the preceding discussion of the status of rodent incisors, the mandibular EDF of the mouse is then di?2 (dp 3-4)M 1-3 (Figure 4D). Figure 5. Occurrence of Heomys (H.), Tribosphenomys (T.), Ivanantonia (I.) and Pappocricetodon (P.) during the Paleocene Eocene times. The extension of the vertical black bars represents the incertitude on relative dating. The loss of dp 3 /P 3 occurred probably during period 1. The loss of dp 4 /P 4 occurred either during period 2 if Ivanantonia belonged to the mouse lineage, or during periods 2 3 if not. The Reduction of the Functional Dental Formula in Rodents When were P 3 and P 4 lost from the functional dentition of rodents in the mouse lineage? From McKenna and Bell [22], the oldest and most primitive rodent known from the fossil record is Heomys from the Palaeocene of China [23] (Figure 5), between 65 and 56 million years (Myr). The mandibular functional QDF of Heomys is di?2 P 3-4 M 1-3. Tribosphenomys from Inner Mongolia and dated between 60 and 52 Myr is also a primitive rodent [24], but its mandibular functional QDF is di?2 P 4 M 1-3. A few million years further along the putative lineage of the modern mouse, the P 4 was absent in Ivanantonia from the early Eocene of Mongolia, dated between 55 to 50 Myr [25, 26]. Ivanantonia is supposed to be the oldest member of the suborder Murida [27] which comprises rodents that already displayed a reduced mandibular dental formula (di?2 M 1-3), similar to that of the modern mouse. However, the maxillary dentition of Ivanantonia has not been discovered now. Hence, the oldest rodent lacking premolars, which is accepted to belong to the mouse lineage, is Pappocricetodon from the Eocene of central China, dated at about 45 Myr [28]. Although the relative datings of these fossil localities are widely spread, it is clear that the Late Paleocene Early Eocene (60 to 50 Myr) is a key period for the reduction of premolars in rodents of the mouse lineage (Figure 5). In this lineage, the loss of the dp 3 /P 3 occurred probably during the Late Paleocene. The loss of the dp 4 /P 4 occurred later, and two cases might be considered: If Ivanantonia belonged to the mouse lineage, dp 4 /P 4 were lost during the earliest Eocene (period 2 of Figure 5); if not, the loss of the dp 4 /P 4 occurred during the Early Middle Eocene, before 45 Myr (period 2-3 of the Figure 5). Putative Correlation Between the Mouse EDF and Evolutionary Data Tribosphenomys developed a dp 4 replaced by a P 4 about 55 Myr ago. Some 10 Myr later, the dp 4 /P 4 were lost from the functional dentition of Pappocricetodon. However, the M 1 of

5 VESTIGIAL TEETH IN MOUSE 133 Pappocricetodon displays a neoformed mesial cingulum, which expanded to form new cusps: the anteroconids. Although the fossil record of early muroid rodents is widely dispersed between 55 and 45 Myr, both the appearance of the anteroconid in the mesial part of the M 1 and the disappearance of the dp 4 /P 4 from the functional dentition occurred during this period (Figure 5). From the fossil record, MS and R2 could respectively be assigned to residual primordia of deciduous functional premolars lost between 60 and 45 Myr ago. Furthermore, a putative involvement of the dp 4 vestigial primordia in the morphogenesis of the M 1 mesial cusps in the modern murine rodents is not ruled out by paleontological data, but more fossil documentation is needed to confirm this process. CONCLUSION Vestigial premolar tooth germs occur in the prospective diastema during early mouse mandibular odontogenesis. MS aborts rapidly (early bud), while R2 is retarded at the late bud stage as a consequence of apoptotic waves, before becoming involved in the mesial M 1 morphogenesis. Many questions remain about the evolutionary process of the dental formula reduction in rodents: Did the aborting vestigial tooth germs regress gradually from bell to lamina, or did they regress suddenly and sporadically? Could some vestigial tooth germs be incorporated in other developing dental structures? These questions may be solved by the identification of molecular mechanisms that control the maintenance and abortion of tooth germs in modern species. ACKNOWLEDGMENTS We thank J.-L. Hartenberger and C. Sutcliffe for critical reading of the manuscript of this article. This work was partially supported by grant A (Grant Agency of the Academy of Sciences of the Czech Republic). REFERENCES [1] Luckett, W.P. (1993). An ontogenetic assessment of dental homologies in therian mammals. In: Mammal Phylogeny, F.S. 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