Do developmental systems preferentially produce certain types of variation that orient phenotypic evolution along preferred directions? At different scales, from the intra-population to the interspecific, the murine first upper molar shows repeated anterior elongation. Using a novel quantitative approach to compare the development of two mouse strains with short or long molars, we identified temporal, spatial and functional differences in tooth signaling center activity, that arise from differential tuning of the activation-inhibition mechanisms underlying tooth patterning. By tracing their fate, we could explain why only the upper first molar reacts via elongation of its anterior part. Despite a lack of genetic variation, individuals of the elongated strain varied in tooth length and the temporal dynamics of their signaling centers, highlighting the intrinsic instability of the upper molar developmental system. Collectively, these results reveal the variational properties of murine molar development that drive morphological evolution along a line of least resistance.

Over time species develop random mutations in their genetic sequence that causes their form to change. If this new form increases the survival of a species it will become favored through natural selection and is more likely to get passed on to future generations. But, the evolution of these new traits also depends on what happens during development. Developmental mechanisms control how an embryo progresses from a single cell to an adult organism made of many cells. Mutations that alter these processes can influence the physical outcome of development, and cause a new trait to form. This means that if many different mutations alter development in a similar way, this can lead to the same physical change, making it ‘easy’ for a new trait to repeatedly occur. Most of the research has focused on finding the mutations that underlie repeated evolution, but rarely on identifying the role of the underlying developmental mechanisms. To bridge this gap, Hayden et al. investigated how changes during development influence the shape and size of molar teeth in mice. In some wild species of mice, the front part of the first upper molar is longer than in other species. This elongation, which is repeatedly found in mice from different islands, likely came from developmental mechanisms. Tooth development in mice has been well-studied in the laboratory, and Hayden et al. started by identifying two strains of laboratory mice that mimic the teeth seen in their wild cousins, one with elongated upper first molars and another with short ones. Comparing how these two strains of mice developed their elongated or short teeth revealed key differences in the embryonic structures that form the upper molar and cause it to elongate. Further work showed that variations in these embryonic structures can even cause mice that are genetically identical to have longer or shorter upper first molars. These findings show how early differences during development can lead to small variations in form between adult species of mice. This study highlights how studying developmental differences as well as genetic sequences can further our understanding of how different species evolved.

• Klíčová slova
• developmental biology, developmental constraint, evo-devo, evolutionary biology, line of least resistance, molar, mouse, rodent,
• MeSH
• biologická evoluce MeSH
• biologická variabilita populace fyziologie   MeSH
• embryo savčí MeSH
• fenotyp MeSH
• moláry anatomie a histologie   růst a vývoj   MeSH
• myši MeSH
• prořezávání zubů fyziologie   MeSH
• signální transdukce MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

When patterns are set during embryogenesis, it is expected that they are straightly established rather than subsequently modified. The patterning of the three mouse molars is, however, far from straight, likely as a result of mouse evolutionary history. The first-formed tooth signaling centers, called MS and R2, disappear before driving tooth formation and are thought to be vestiges of the premolars found in mouse ancestors. Moreover, the mature signaling center of the first molar (M1) is formed from the fusion of two signaling centers (R2 and early M1). Here, we report that broad activation of Edar expression precedes its spatial restriction to tooth signaling centers. This reveals a hidden two-step patterning process for tooth signaling centers, which was modeled with a single activator-inhibitor pair subject to reaction-diffusion (RD). The study of Edar expression also unveiled successive phases of signaling center formation, erasing, recovering, and fusion. Our model, in which R2 signaling center is not intrinsically defective but erased by the broad activation preceding M1 signaling center formation, predicted the surprising rescue of R2 in Edar mutant mice, where activation is reduced. The importance of this R2-M1 interaction was confirmed by ex vivo cultures showing that R2 is capable of forming a tooth. Finally, by introducing chemotaxis as a secondary process to RD, we recapitulated in silico different conditions in which R2 and M1 centers fuse or not. In conclusion, pattern formation in the mouse molar field relies on basic mechanisms whose dynamics produce embryonic patterns that are plastic objects rather than fixed end points.

• MeSH
• biologické modely * MeSH
• chemotaxe MeSH
• epitel embryologie   metabolismus   MeSH
• mutantní kmeny myší MeSH
• myši MeSH
• receptor Edar genetika   metabolismus   MeSH
• rozvržení tělního plánu * MeSH
• signální transdukce * MeSH
• vlasy, chlupy embryologie   MeSH
• vývojová regulace genové exprese MeSH
• zubní zárodek embryologie   metabolismus   MeSH
• zuby embryologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Edar protein, mouse MeSH Prohlížeč
• receptor Edar MeSH

The Eda pathway ( Eda, Edar, Edaradd) plays an important role in tooth development, determining tooth number, crown shape, and enamel formation. Here we show that the Eda pathway also plays a key role in root development. Edar (the receptor) is expressed in Hertwig's epithelial root sheath (HERS) during root development, with mutant mice showing a high incidence of taurodontism: large pulp chambers lacking or showing delayed bifurcation or trifurcation of the roots. The mouse upper second molars in the Eda pathway mutants show the highest incidence of taurodontism, this enhanced susceptibility being matched in human patients with mutations in EDA-A1. These taurodont teeth form due to defects in the direction of extension of the HERS from the crown, associated with a more extensive area of proliferation of the neighboring root mesenchyme. In those teeth where the angle at which the HERS extends from the crown is very wide and therefore more vertical, the mutant HERSs fail to reach toward the center of the tooth in the normal furcation region, and taurodont teeth are created. The phenotype is variable, however, with milder changes in angle and proliferation leading to normal or delayed furcation. This is the first analysis of the role of Eda in the root, showing a direct role for this pathway during postnatal mouse development, and it suggests that changes in proliferation and angle of HERS may underlie taurodontism in a range of syndromes.

• Klíčová slova
• ectodermal dysplasia, ectodysplasins, epithelium, furcation defects, periodontium, tooth,
• MeSH
• abnormality zubů genetika   MeSH
• dítě MeSH
• ektodysplasiny genetika   MeSH
• fenotyp MeSH
• kavita zubní dřeně abnormality   MeSH
• lidé MeSH
• mladiství MeSH
• moláry abnormality   embryologie   MeSH
• myši MeSH
• odontogeneze genetika   MeSH
• rentgenová mikrotomografie MeSH
• signální transdukce MeSH
• zubní kořen abnormality   embryologie   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• EDA protein, human MeSH Prohlížeč
• Eda protein, mouse MeSH Prohlížeč
• ektodysplasiny MeSH

Tooth development has attracted the attention of researchers since the 19th century. It became obvious even then that morphogenesis could not fully be appreciated from two-dimensional histological sections. Therefore, methods of three-dimensional (3D) reconstructions were employed to visualize the surface morphology of developing structures and to help appreciate the complexity of early tooth morphogenesis. The present review surveys the data provided by computer-aided 3D analyses to update classical knowledge of early odontogenesis in the laboratory mouse and in humans. 3D reconstructions have demonstrated that odontogenesis in the early stages is a complex process which also includes the development of rudimentary odontogenic structures with different fates. Their developmental, evolutionary, and pathological aspects are discussed. The combination of in situ hybridization and 3D reconstruction have demonstrated the temporo-spatial dynamics of the signalling centres that reflect transient existence of rudimentary tooth primordia at loci where teeth were present in ancestors. The rudiments can rescue their suppressed development and revitalize, and then their subsequent autonomous development can give rise to oral pathologies. This shows that tooth-forming potential in mammals can be greater than that observed from their functional dentitions. From this perspective, the mouse rudimentary tooth primordia represent a natural model to test possibilities of tooth regeneration.

• Klíčová slova
• 3D reconstruction, Tooth, development, human, mouse, odontogenesis,
• MeSH
• biologická evoluce MeSH
• dentice MeSH
• diastema embryologie   MeSH
• hybridizace in situ metody   MeSH
• lidé MeSH
• myši MeSH
• odontogeneze * genetika   fyziologie   MeSH
• počítačové zpracování obrazu MeSH
• regenerace MeSH
• zobrazování trojrozměrné metody   MeSH
• zuby přespočetné embryologie   MeSH
• zuby embryologie   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

It is known from paleontology studies that two premolars have been lost during mouse evolution. During mouse mandible development, two bud-like structures transiently form that may represent rudimentary precursors of the lost premolars. However, the interpretation of these structures and their significance for mouse molar development are highly controversial because of a lack of molecular data. Here, we searched for typical tooth signaling centers in these two bud-like structures, and followed their fate using molecular markers, 3D reconstructions, and lineage tracing in vitro. Transient signaling centers were indeed found to be located at the tips of both the anterior and posterior rudimentary buds. These centers expressed a similar set of molecular markers as the "primary enamel knot" (pEK), the signaling center of the first molar (M1). These two transient signaling centers were sequentially patterned before and anterior to the M1 pEK. We also determined the dynamics of the M1 pEK, which, slightly later during development, spread up to the field formerly occupied by the posterior transient signaling center. It can be concluded that two rudimentary tooth buds initiate the sequential development of the mouse molars and these have previously been mistaken for early stages of M1 development. Although neither rudiment progresses to form an adult tooth, the posterior one merges with the adjacent M1, which may explain the anterior enlargement of the M1 during mouse family evolution. This study highlights how rudiments of lost structures can stay integrated and participate in morphogenesis of functional organs and help in understanding their evolution, as Darwin suspected long ago.

• MeSH
• biologické modely MeSH
• časové faktory MeSH
• fluorescenční mikroskopie metody   MeSH
• hybridizace in situ MeSH
• mandibula embryologie   růst a vývoj   metabolismus   MeSH
• moláry embryologie   růst a vývoj   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• odontogeneze * MeSH
• proteiny hedgehog genetika   metabolismus   MeSH
• techniky tkáňových kultur MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• zobrazování trojrozměrné metody   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• proteiny hedgehog MeSH
• Shh protein, mouse MeSH Prohlížeč
• zelené fluorescenční proteiny MeSH

An understanding of the factors that promote or inhibit tooth development is essential for designing biological tooth replacements. The embryonic mouse dentition provides an ideal system for studying such factors because it consists of two types of tooth primordia. One type of primordium will go on to form a functional tooth, whereas the other initiates development but arrests at or before the bud stage. This developmental arrest contributes to the formation of the toothless mouse diastema. It is accompanied by the apoptosis of the rudimentary diastemal buds, which presumably results from the insufficient activity of anti-apoptotic signals such as fibroblast growth factors (FGFs). We have previously shown that the arrest of a rudimentary tooth bud can be rescued by inactivating Spry2, an antagonist of FGF signaling. Here, we studied the role of the epithelial cell death and proliferation in this process by comparing the development of a rudimentary diastemal tooth bud (R(2)) and the first molar in the mandibles of Spry2(-/-) and wild-type (WT) embryos using histological sections, image analysis and 3D reconstructions. In the WT R(2) at embryonic day 13.5, significantly increased apoptosis and decreased proliferation were found compared with the first molar. In contrast, increased levels of FGF signaling in Spry2(-/-) embryos led to significantly decreased apoptosis and increased proliferation in the R(2) bud. Consequently, the R(2) was involved in the formation of a supernumerary tooth primordium. Studies of the revitalization of rudimentary tooth primordia in mutant mice can help to lay the foundation for tooth regeneration by enhancing our knowledge of mechanisms that regulate tooth formation.

• MeSH
• adaptorové proteiny signální transdukční MeSH
• apoptóza * MeSH
• hybridizace in situ MeSH
• intracelulární signální peptidy a proteiny MeSH
• membránové proteiny genetika   fyziologie   MeSH
• morfogeneze MeSH
• myši knockoutované MeSH
• myši MeSH
• proliferace buněk * MeSH
• protein-serin-threoninkinasy MeSH
• zuby růst a vývoj   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• intracelulární signální peptidy a proteiny MeSH
• membránové proteiny MeSH
• protein-serin-threoninkinasy MeSH
• Spry2 protein, mouse MeSH Prohlížeč