Author Manuscript NIH Public Access 1,*, Vladimir Soukup ... · However, did the first odontode appear within the evolving oro- pharyngeal cavity for food breakdown during the transition

The Odontode Explosion: The origin of tooth-like structures invertebrates

Gareth J. Fraser1,*, Robert Cerny2, Vladimir Soukup2, Marianne Bronner-Fraser3, and J.Todd Streelman4,*1 Department of Animal and Plant Sciences, University of Sheffield, UK2 Department of Zoology, Charles University in Prague, Czech Republic3 Division of Biology, California Institute of Technology, Pasadena, USA4 School of Biology and Petit Institute for Bioengineering and Biosciences, Georgia Institute ofTechnology, Atlanta, USA

AbstractWe integrate recent data to shed new light on the thorny controversy of how teeth arose inevolution. Essentially we show (a) how teeth can form equally from any epithelium, be itendoderm, ectoderm or a combination of the two and (b) that the gene expression programs of oralvs. pharyngeal teeth are remarkably similar. Classic theories suggest that (i) skin denticles evolvedfirst and odontode-inductive surface ectoderm merged inside the oral cavity to form teeth (the‘outside-in’ hypothesis) or that (ii) patterned odontodes evolved first from endoderm deep insidethe pharyngeal cavity (the ‘inside-out’ hypothesis). We propose a new perspective that viewsodontodes as structures sharing a deep molecular homology, united by sets of co-expressed genesdefining a competent thickened epithelium and a collaborative neural crest derivedectomesenchyme. Simply put, odontodes develop ‘inside and out,’ wherever and whenever theseco-expressed gene sets signal to one another. Our perspective complements the classic theoriesand highlights an agenda for specific experimental manipulations in model and non-modelorganisms.

Keywordsodontode; dentition; neural crest; taste bud; gene network

IntroductionEvolving odontodes: On the origins of the vertebrate dentition

How and when tooth-like units (odontodes) originated during vertebrate evolution continuesto cause a stir among paleontologists and evolutionary developmental biologists [9].Odontodes are classified here from Ørvig’s description [4,5] as simply all structures thatcomprise a mineralized hard tissue unit consisting of attachment bone, dentine (with greathistological diversity early in the fossil record [4]) sometimes with a superficial layer ofenamel/enameloid, formed from a single papilla (see also [1,9,10]). Odontodes are by far themost readily fossilized vertebrate structures and are heavily used for early phylogeneticreconstructions [10]. Despite the rich record of fossil tooth-like structures, the actual

*Corresponding authors - [GJF] [email protected], [JTS] [email protected].

NIH Public AccessAuthor ManuscriptBioessays. Author manuscript; available in PMC 2011 February 7.

Published in final edited form as:Bioessays. 2010 September ; 32(9): 808–817. doi:10.1002/bies.200900151.

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sequence of events accounting for the evolution of oral versus dermal odontodes continuesto evoke controversy. Uncertainty arises with conflicting, although not coincidental, fossilevidence of (i) jawless vertebrates with an oro-pharyngeal tooth apparatus (conodonts [10–13]), (ii) jawless vertebrates with both skin denticles and patterned pharyngeal tooth whorls(thelodonts [14]) and (iii) still other jawless vertebrates with an extensive dermal skeletonornamented with odontodes, lacking any oropharyngeal denticles (e.g. ostracoderms[1,10,15]). Some evidence suggests that the first jawed vertebrates (albeit derived,placoderms [16–18]) possessed teeth on their jaws (gnathal bones), ordered denticles on thebone of the posterior pharyngeal wall, as well as dermal tubercules.

Debate about the appearance and evolution of odontodes during early vertebrate evolution isfirmly rooted in the classic problem of anatomical homology [9,19,20]. Odontodes can befound in multiple locations around the body of lower vertebrates, whether covering thedermal surface as in extant sharks and rays, as a dentition in oral and pharyngeal locations,or lining the oro-pharyngeal cavity associated with gill arches. The perceived homology ofall odontodes is based on palaeontological evidence, structural and developmentalsimilarities [1,2,21,22]. According to Reif [1,21], the highly specialized mode of formationmakes it unlikely that odontodes convergently evolved in various vertebrate groups. Notablyand without contention, teeth and tooth-like structures evolved in vertebrates ahead, andindependently, of the oral jaws [23,24]. Thus, odontodes had their origins in ancient jawless(agnathan) vertebrates [9]. However, did the first odontode appear within the evolving oro-pharyngeal cavity for food breakdown during the transition to more predatory behavior -- ordid the first tooth-like structures appear as external dermal armour in a predator-richenvironment?

Two main theories polarize the field: the traditional view, that skin denticle competentectodermal-epithelium folded and integrated into the mouth to provide the inductivecapacity for teeth – the ‘outside-in theory’ – is contested by the ‘inside-out theory’ thatteeth, born from endoderm, originated in the posterior pharynx of jawless vertebrates withdental potential co-opted anteriorly to oral jaws during gnathostome evolution [23]. In thisarticle, we discuss the main theories of tooth and general odontode origin, and develop anew perspective, based on recent data from evolutionary developmental biology, that pushesbeyond contemporary debate. We propose that odontodes evolved as the gene regulatorynetworks (GRNs) of basic epithelial (ectoderm or endoderm) structures combined with thoseof migrated neural crest cells. We hope to galvanize a research effort that seeks tounderstand the development of placode-like elements in extant organisms as a means to inferdeep molecular homology uniting all odontodes, whatever their location.

Current hypotheses that explain the evolution of teethOutside-in model of tooth evolution

According to the classical theories [1,25–27], collectively the ‘outside-in’ model, teeth cameto reside within the oral cavity of jawed vertebrates when odontode-competent tissue layermoved there from the body surface. This view is largely based on the anatomicalresemblance of shark skin denticles to teeth, although they do not grade into each other[28,29] and no continuous transition exists between the two structures [21]. The ‘outside-in’theory posits the following principles: 1) odontodes originated from ectoderm, on theexternal surface of an organism in the form of skin denticles; 2) in order for oral teeth tohave evolved, ectodermal cells that form denticles on the surface must have mixed andincorporated into the oro-pharyngeal cavity during development; 3) only ectodermal cellshave the capacity to form odontodes and thus all derivatives must have originated viaectodermal organogenesis. Teeth are, under this theory, modified skin denticles [30–32] (seeFigure 1: A1). According to this model, the major difference between a skin denticle and a

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tooth is their locus of formation. Denticles form superficially on the skin surface, arisingdirectly at the epithelium/mesenchyme interface, whereas teeth form inside the oro-pharyngeal cavity, at positions of future tooth-bearing bones and develop from a specializedepithelial invagination called the dental lamina [1] or from a similar structure called theodontogenic band [33–36].

To substantiate the ‘outside-in’ scenario, fossil evidence would be required to show that theearliest odontodes were located externally in organisms without oro-pharyngealcounterparts. Secondly, odontodes in fossil and extant creatures should form primarily onregions derived from ectoderm. Classically, palaeontological support for this theory comesfrom extinct jawless vertebrates, for example, ostracoderms [10,15] and thelodonts [37], andfrom both fossil and recent elasmobranchs (sharks and rays) (see “evolving odontodes”section and citations therein). The caveat here is that in both thelodonts and elasmobranchs,odontodes were/are concurrently located on the skin and inside the pharynx [28,29]. Withrespect to ectodermal origins, it is nearly impossible to infer such detail from fossils andsurprisingly difficult to ascertain in extant organisms (see below, this applies equally to the‘inside-out’ model).

Inside-out model of tooth evolutionThe ‘inside-out’ model states that teeth first appeared in the endoderm-dominated oro-pharyngeal cavity of jawless vertebrates [28]. This hypothesis was initially proposed bySmith and Coates [14,23,29] who argued that sets of patterned odontodes (prototype toothsets) first evolved in the pharyngeal cavity. It was from the pharyngeal cavity that toothcompetence and pattern was coopted anteriorly to the oral jaw margins of gnathostomes[14,23]. However, neither the mechanism of pattern co-option, nor the role of neural crestand their derived cells (ectomesenchyme) was discussed.

The ‘inside-out’ theory of tooth evolution poses the following: 1) tooth sets originated insidethe endoderm-dominated posterior pharynx of now extinct jawless vertebrates; 2)subsequently, the molecular controls for competence were co-opted anteriorly to the oraljaws; 3) teeth and skin denticles appeared independently from alternative tissue layers,endoderm and ectoderm, respectively; 4) the unique patterning mechanism for a dentitionlies specifically within the endoderm of the oro-pharynx (this includes the boundary zonewhere endoderm is juxtaposed with ectoderm in the oral cavity) [28], that is, given thedistinction that teeth are well organized or ‘patterned’ whereas denticles are more randomlydistributed. According to the ‘inside-out’ hypothesis, denticles are not teeth and vice versa(see Figure 1B). To substantiate this scenario, fossil evidence would be required to showthat the earliest odontodes were located internally in early vertebrates without anysuperficial counterparts. Furthermore, odontodes in fossil and extant vertebrates should formprimarily from endoderm.

A ‘modified’ outside-in theoryRecently, a ‘modified outside-in hypothesis’ has been suggested [38]. In concordance withthe classic ‘outside-in’ theory, evolutionary precursors of teeth are believed to be epidermal(ectodermal) denticles, where teeth evolved only after an odontogenic competent ectodermaltissue had mixed inside via the mouth and each of the gill slits [38]. In contrast to theoriginal ‘outside-in’ scenario where teeth develop solely from ectoderm [1], this ‘modified’hypothesis allows that the initial odontogenic potential of the ectoderm may have beensubsequently transferred to endoderm upon contact and cell mixing. Direct contact of bothepithelial germ layers is thus a prerequisite for teeth to form. The arguments for this are asfollows: 1) experimental and in vitro studies indicate that both ectoderm and endoderm cellsare needed for teeth to develop; however, until now these studies were undertaken mostly on



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salamanders [39–41]; 2) classical observations on the ecto-endoderm boundaries within thepharyngeal cavity of cypriniform fishes revealed complex epithelial morphodynamics withpharyngeal teeth developing from the endoderm epithelia, with the ectoderm lining in closeproximity [42,43] (see Figure 1: A2). Further support for this ‘modified’ hypothesis isoffered by the fact that pharyngeal teeth are only found in species with gill slits and that,accordingly, pharyngeal teeth are absent in tetrapods, coincident with the retained closure ofthe pharyngeal cavity [38]. However, in some tetrapods like salamanders or frog tadpoles,gill slits remain open, but no pharyngeal teeth develop [44,45].

Evidence of odontode evolution from the fossil recordThe earliest mineralized skeleton known from the fossil record was probably present in agroup of animals known as the conodonts [13,46]. Conodonts are extinct eel-like jawlessvertebrates that did not possess a dermal armor but did contain an intricately patterned seriesof odontodes throughout the oro-pharyngeal cavity [11]. The conodonts appeared at thedawn of vertebrates and it is possible that they brought with them the first vertebratedentition. Although conodont relationships remain contentious, the true conodonts(Euconodonta) are thought to have possessed a dentition putatively homologous to thevertebrate oro-pharyngeal dentition, composed of dentine and enamel-like tissues [9,10,12].

Conodonts may provide evidence for an oro-pharyngeal location of the earliest odontode,but their uncertain phylogenetic relationships do not close the argument. Further fossilevidence has been discussed in this context. A subset of another jawless vertebrate group,the Thelodonts, exemplified by the species Loganellia scotica, possess both skin denticles,similar in structure to extant elasmobranch skin denticles, and oro-pharyngeal tooth whorlsthat are uniquely patterned [14,23,37]. This diverse array of odontodes within one speciessuggests that there may be a distinction between these ‘inside’ and ‘outside’ populations; aspecific oro-pharyngeal pattern links internal odontodes [28]. Loganellia fossils furthersupport the notion that this unique ‘dental’ pattern for pharyngeal odontodes originated priorto functional jaws, [14,23,28] both oral and pharyngeal [47]. Thus whatever their ancestralhomology, odontodes of the oro-pharyngeal cavity and the dermis might develop underalternative patterning mechanisms. This is the main evidence used by Smith and Coates [14]to suggest that pharyngeal odontodes developed independently from epidermal odontodes(Figure 1B).

The closest fossil relatives to the gnathostomes among jawless vertebrates are all covered bylarge dermal plates often covered by odontodes[1,10,15]. Thus, for example, the earlyOrdovician fossils like Arandaspis or Anatolepis might be seen as excellent support for the‘outside-in’ hypothesis, since these animals undoubtedly possessed odontodes on their outersurfaces with none situated internally. Moreover, in some heterostracans, another group offossil jawless vertebrates, external headshield structures have been found to intergrade withsome internally situated oro-pharyngeal denticles[48]. These latter fossil data thus do notsupport a distinction between oral and skin odontodes.

To sum up, current hypotheses about odontode origins have pushed the fossil record as faras it will go. Phylogenetic uncertainty, issues of anatomical homology and dubious inferenceof germ layer (ectoderm vs endoderm) from extinct organisms make it difficult todifferentiate between even the well-delineated predictions of the ‘outside-in’ vs. ‘inside-out’theories. We thus turn our attention to a synthesis of recent and sometimes surprising data,collected from extant model and non-model organisms, to address the common ingredientsfor seemingly diverse odontodes.



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New perspectivesThe complex ectoderm-endoderm boundary and the epithelial ingredients for teeth

Definitive evidence of teeth originating from a single germ layer in extant vertebrates wouldbe ideal to differentiate between ‘outside-in’ vs. ‘inside-out’ scenarios; however, the realityis less straightforward than once suspected. In the vertebrate head, ectoderm and endodermmeet at the prospective mouth region and between each pharyngeal arch: where ectodermalways forms the outer and endoderm the inner epithelial lining[49,50]. Themorphodynamics of these epithelial linings during embryogenesis is complex and not fullyunderstood. In the mouth, the natural ectoderm-endoderm boundary is formed by thejuxtaposition of the ectoderm layer of the stomodeal invagination and the endoderm layer ofthe anterior alimentary canal, called the oro-pharyngeal membrane[44,51]. During thecourse of development the oro-pharyngeal membrane thins, cell number is reduced, thebasement membrane adjoining the ectoderm and endoderm disappears and eventually breaksthrough [52]. Strikingly similar conditions also hold for the ectoderm-endoderm contactareas between individual pharyngeal pouches and corresponding pharyngeal clefts wherethese epithelia together form so-called branchial membranes (e.g.[49,50,53–56]). As in thecase of oral development, perforation of the branchial membranes probably causes a loss ofdefinitive ectoderm-endoderm boundaries. Subsequent cell rearrangements potentially occurto produce a cryptic distribution of these epithelia [38,43],.

Recent observations challenge the classic view (e.g. [57]) of a static and definitiveectoderm-endoderm boundary after the perforation of oro-pharyngeal membranes. InXenopus, for example, intercalation of ectoderm and endoderm occurs prior to theperforation of the oro-pharyngeal membrane and such mixing probably reflects a loss of theascribable germ layer identity in these cells [52]. In urodele amphibians, contrary to thecommon vertebrate scheme, oral ectoderm does not invade to form a stomodeum, but furtherectoderm ingrowth still occurs leading to epithelia of double germ layer origin[42]. In theMexican axolotl, the basal layer of the oral ectoderm moves internally to cover the surfaceof the mouth endoderm, whereas the apical layer remains outside/at place. The breaking ofthe oro-pharyngeal membrane and the opening of the mouth leads to the formation ofepithelia, which consist of an ectodermal basal layer and an endodermal apical layer [42].Interestingly, it was suggested long ago that during the formation of gill slits in carp,pharyngeal ectoderm and endoderm undergo comparable morphodynamics, but result in theformation of double germ layer epithelia with an apical ectoderm layer and a basalendoderm layer (i.e., Reciprocal situation to axolotl oral epithelia) [43].

Likewise, the ecto-endoderm boundary is not easily recognized in dental epithelia. In theMexican axolotl, the only animal in which the germ layer origin of teeth has been analysedby means of lineage tracing [42,58], tooth epithelia are derived from both ectoderm andendoderm. In fact, some teeth are found to be of a dual origin. In the case of the mousedentition, commonly considered ectodermal [59,60], endoderm cells have been fate-mappedadjacent to tooth buds [61]. In zebrafish, an animal with no oral but only pharyngeal teeththat are considered to develop from endoderm epithelia (e.g. [62,63]), some have speculatedthat the dentition might be derived from endoderm with some pharyngeal ectodermepithelial cells in close proximity [38]. According to available data, vertebrate teeth can bederived equally from ectoderm as well as endoderm cells. Moreover, the case of theMexican axolotl, where a single tooth bud can be of dual epithelial origin [42], implies that“ectodermal” and “endodermal” teeth might not differ at any substantial level.



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Do all odontodes require neural crest-derived ectomesenchyme?It has long been supposed that vertebrate odontodes, whether oro-pharyngeal teeth or skindenticles, require reciprocal cell signaling between an epithelium (see last section) andunderlying mesenchymal cells (ectomesenchyme) that originate from migrated neural crest[39,40,64]. Interestingly, according to Reif’s initial ideas [1], odontodes evolved only afterneural crest cells were able to migrate and when an inductive interaction occurred betweenectodermal epithelia and mesenchyme (although we now know that endodermal epitheliumshould be included in this statement). It is generally agreed that cells with the properties ofneural crest were present prior to the origin of vertebrates [65–68], and that during the earlyevolution of vertebrates the neural crest cell lineage was expanding its repertoire ofmigratory derivatives [65–67].

We now understand the molecular interactions that control the earliest stages of neural crestdevelopment. A neural crest gene regulatory network (ncGRN), thought to be conservedamong vertebrates[69], guides neural crest development from induction at the neural plateborder to migration to ultimate differentiation of distinct cell populations including neurons,glia, pigment, bone, cartilage and dentine (this last step is poorly understood). This ncGRNinvolves interacting signals including Wnts, BMPs, and FGFs, and transcriptional regulatorsincluding Msx1/2, Zic and Pax3/7, in sequential modules (e.g., the neural crest specifiermodule, which includes the transcription factors Snail2, Sox9/10, FoxD3, N-Myc[68,70–73]). These modules co-regulate each other, as well as downstream effector genes thatconfer properties such as multipotency, the ability to undergo an epithelial to mesenchymaltransition, extensive migratory capacity and subsequently the ability to differentiate intonumerous and distinct derivatives depending upon their final location.

Despite our understanding of gene networks in early neural crest development, the signalsand factors governing differentiation of cranial (or any other) neural crest cells to competentectomesenchyme are relatively unknown [74]. It is clear that FGFs are required for theectomesenchymal cell lineage within the pharyngeal arches, at least[65,74]. Teeth requireectomesenchyme derived from cranial neural crest[75,76], but the molecular basis of theneural crest to ectomesenchyme transition is not fully known. Although the neural crest-derived nature of dental ectomesenchyme is now well documented in the mouse, the exactorigin of the mesenchymal component for osteichthyan (i.e. actinopterygian and basalsarcopterygian fish) dermal scales and chondrichthyan skin denticles is not. Studies suggestthat the formation of the dermal skeleton, at least in osteichthyan and chondrichthyan fishes,uses trunk neural crest-derived mesenchyme [2,22,30,77,78]; however definitive data isneeded to address whether trunk and/or cranial neural crest are necessary and/or sufficient,or whether mesodermal mesenchymal cells and their associated GRN(s) are involved.

A ‘dental gene network’ and odontode deep homologyRecent data (reviewed above) demonstrate that teeth form from epithelium of ectoderm,endoderm and even a combination of the two, when properly combined with neural crestderived ectomesenchyme. These observations suggest that the cellular derivation of dentalepithelium is not an informative means to sort between types of teeth. Using similar logic,Fraser and colleagues[47] asked if the oral (presumed ectodermal) and pharyngeal(presumed endodermal) teeth of cichlid fishes developed under the control of similar ordifferent gene co-expression groups (CEG). Despite important differences between oral andpharyngeal teeth (i.e., pharyngeal teeth express Hox genes), the main observation was that,regardless of location in the oro-pharyngeal cavity, teeth develop using a common set ofgenes. Integrating across other studies of vertebrate dentitions (both oral and pharyngeal),the authors delineated a ‘core’ dental gene set used to make all teeth. This dental CEG



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includes the well-known molecules β-catenin, bmp2, bmp4, dlx2, eda, edar, fgf3, fgf10,notch2, pitx2, runx2, and shh (Table 1).

Considering these recent reports in combination, a slightly different picture of tooth originsemerges. Developmental data from the axolotl[42] and molecular data from fishes[33,35,36,79–83] strongly suggest that the germ-layer origin of dental epithelium does notmatter and that teeth derived from ectoderm, endoderm and a mixed origin, exhibit similarmorphogenesis. Moreover, the expression of genes does not differ significantly between oral(supposedly ectoderm) and pharyngeal (supposedly endoderm) dentitions in osteichthyans[33,35,36,47,79–83]. These data imply that we should not view teeth as originating from anysingle cell type in any single place. Rather, teeth should be seen as derivatives of epithelial-mesenchyme interplay driven by reciprocal interactions among signaling networks (Figure2). Teeth develop wherever such networks are expressed, regardless of germ layerdistribution. Such a viewpoint holds that there is strong molecular homology among all teeth(and perhaps all odontodes) and that one of the goals of future research is to solve thestructure of the networks involved. Note that gene expression data for odontodes are derivedalmost exclusively from dentitions; it therefore remains to be determined whether skindenticles exhibit a similar degree of shared gene expression (Table 1).

An ‘inside and out’ model of odontode evolutionary developmentThe classic hypotheses described above (‘outside-in,’ ‘inside-out,’ and the ‘modifiedoutside-in’ hypotheses) rely heavily on phylogenetic reconstruction of ancient events, fossilmaterial and a false dichotomy between endoderm and ectoderm dental epithelium. Here weattempt to push beyond these classic arguments by proposing a new perspective informed bynew data. We suggest that odontodes evolved when and wherever epithelial and neural crestderived ectomesenchymal gene networks came into association during development (Figure2). We call this the ‘inside and out’ model to (i) focus attention away from an argumentabout primacy of location and/or cell type and (ii) clarify that an appreciation of deephomology among odontodes may broaden our evolutionary understanding of thesestructures, as with animal appendages [84–86].

This alternative perspective of odontode development and evolution has the advantage thatsome of its tenets should be experimentally testable in extant organisms (see Table 1; Figure3 and below). Our perspective incorporates important aspects of the classic hypotheses. Weinfer homology among all odontodes as does the ‘outside-in’ theory, although we favor deepmolecular homology. Similarly, we agree with the idea of co-option of patterninginformation, as stated by the ‘inside-out’ theory. Our proposal is focused on: 1) thepresumptive odontode gene regulatory network (oGRN) as the homologous unit rather thanspecific cell populations; 2) the inference that tissue mixing and incorporation betweenendoderm and ectoderm to ‘place’ the cellular competence for odontode development mayhave occurred, but is unnecessary; 3) the essential components for odontode formation areneural crest-derived ectomesenchyme and any epithelium; 4) the suggestion that anepithelial placode co-expression group (epCEG) linking all odontodes may have had anancestral sensory function (Figure 3). Thus, we speculate that the sequence of events was asfollows: an epCEG together with the neural crest-derived mesCEG came to form the oGRN,common to all odontodes regardless of location; this common oGRN within the oro-pharyngeal region formed the dental GRN [47] (Figures 2, 3).

It is plausible to think that a gene co-expression group was already acting within a thickenedepithelial placode (epCEG) for a sensory papillae-like developmental fate (similar to tastebud, Table 1 and Figure 3). Thus we speculate that these sensory papillae-like structuresevolved ahead of both taste buds and odontodes. With the inclusion of signals fromdifferentiating neural crest (mesCEG), the fate possibilities for these precursor structures



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were greatly enhanced. Presently, we know little of the functional interrelationships of theseco-expression groups leading to possible precursor gene networks. De novo ‘instigatornetworks’ are unlikely. Rather, the advent of odontodes was probably the result of‘innovative consolidation’ (where two or more preexisting signaling networks joined to forma new collaborative network) of two or more separate regulatory networks triggered by thewandering neural crest. We envision that an odontode gene network (oGRN) evolved as theassociation of: 1) an ‘epithelial thickening/placode’ gene co-expression group (epCEG); inplace due to sensory structure development on both the epidermis, for example, related toelectro-receptive organs or lateral line extensions and within the oro-pharynx; for exampleduring the development of taste bud-like structures; and 2) elements of a neural crest-derived ectomesenchyme gene co-expression group (mesCEG) [69,70,72]. This may havegalvanized the evolution of odontodes for both oro-pharyngeal feeding (teeth) and epidermalprotection/armour (denticles) (Figure 3).

Agenda for future discoveryDuring the course of evolution, single surface odontodes formed in the epidermis, retainedtheir function and were modified into odontocomplexes or scales for hydrodynamicenhancements and armour, and those forming in the oro-pharyngeal cavity became utilizedfor food-processing activities and predatory advantage. The common question “How didskin denticles become teeth or vise versa?” is difficult to answer given the currentconstraints of the data. We hope to shift thinking by suggesting that gene networks activeacross multi-cell lineages (ectoderm, endoderm, and neural crest) instigated the evolution ofodontodes within previously unrelated tissues, in numerous locations.

Notably, our perspective should allow inference of the necessary, sufficient and distinctcomponents of the epCEG, the mesCEG, and thus the oGRN (Table 1, Figure 3).Specifically, research might be directed toward a deeper understanding of the molecularhomology among all odontodes, whether the skin denticles of sharks, the scales of fishes, orthe molar teeth of mammals. For instance, we observe that many of the genes expressed aspart of the ‘core’ dental network are active in the initiation of teleost scales, and sensorystructures like the cephalic lateral line placodes and taste buds (Table 1, Figure 3; GJF/JTSunpublished).

We are intrigued by the idea that the epCEG for odontodes had as its precursor an ancientsensory structure similar to a taste bud. Teeth and oro-pharyngeal denticles are co-localizedwith taste buds (and related papillae) throughout the oro-pharyngeal cavity ofchondrichthyan (pers. obs.[3]) and osteichthyan fish[33,36,87,88] and it is becoming clearthat both of these now-distinct structures share a similar developmental ground plan (Table1,Figure 3). When co-localised, teeth and taste buds both develop from a thickenedepithelial placode, from a common epithelium, with teeth forming ahead of taste buds intime[33]. Co-localisation is decoupled in some vertebrates, like mammals. Decoupled co-localisation is also observed in select teleost fish, for example, zebrafish, which have lostoral teeth but have retained the capacity to develop oral taste buds and gained further extra-oral sites[89], although teeth and taste buds are co-localised in the zebrafish posteriorpharynx. Taste buds develop from (ectodermal and endodermal) epithelia and it is somewhatunclear what signals are necessary from the underlying mesenchyme for their development[58,90]. Taste buds might not recruit neural crest-derived mesenchyme for theirpatterning[90] although mesenchyme might be involved in directing epithelial evaginationsand attracting innervation[91]. Innervation is not required for the initiation of teeth[92] ortaste buds[93,94] – in fact, first-generation teeth lack innervation in non-mammalianvertebrates[95] – but it is necessary for subsequent morphogenesis and continuedreplacement[96].



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Importantly, a guidance mechanism exists during development that could account for (i) thelink between taste bud-like sensory structures and odontodes and (ii) the transition to tooth/odontode from a sensory precursor. Neuropilin and semaphorin molecules are known torepel/attract both axons and neural crest cells in vertebrate embryos[97–99]. We speculatethat guidance mechanisms of this type, already in place for axonal navigation, were co-optedby neural crest cells during the elaboration of vertebrate odontodes. This may in fact be themeans with which pioneer neural crest cells ‘found’ the ancestral epithelial placodes. It mustbe clarified that we are not suggesting teeth evolved from taste buds, but rather that bothodontodes and taste buds may share a common primitive sensory unit that relied on thedevelopment of an innervated epithelial placode (Figure 3B).

Another vital question for future research is the degree to which the ncGRN and the reactivemesenchyme (ectomesenchyme - mesCEG) provide a necessary trigger/cue to push the fateof a taste bud-like sensory structure toward an odontode. A dissection of the molecularcontrols that distinguish a tooth from a taste bud after the formation of the commonepithelial thickening is necessary for these future investigations. Such questions can beaddressed via manipulation studies. For instance, can we shift the fate of taste bud primordiaduring early development toward dental/odontode fate, via collective over-expressiontechniques, artificial (in vitro) cell combination or tissue recombination assays?Interestingly, loss of Follistatin[91] (a mesenchymal, secreted polypeptide that regulates thesize, patterning and innervation of taste papillae) in mice can lead to an invaginated lingualepithelium (dysplastic epithelium) into the underlying mesenchyme, reminiscent of theinvaginated epithelial thickening during tooth initiation (taste epithelia evaginate to producethe characteristic superficial papillae). Follistatin is expressed during tooth development andcontributes to dental epithelial morphogenesis[100] and enamel formation, naturallyinhibiting ameloblast differentiation[101]. It will be important to understand how Follistatinfunctions in dentitions co-localized with taste buds, such as those in most non-mammalianvertebrates.

In addition, can we force the neural crest signaling cascades (once identified) to induceodontode fate from endodermal and ectodermal epithelia in isolation? Furthermore, can wedefer the promotion of an odontode epithelial thickening for the development of a basic,taste bud-like sensory structure? We note a particularly promising candidate from the datapresented in Table 1; sox2 is expressed solely in taste buds and the cephalic lateral line andappears to label the sensory nature (neuromast cells) of these epithelial placodes.Advancement will also involve dissection of the replacement capacities of each of thesestructures, teeth, denticles and taste buds. Can the molecular biology of renewal andregeneration be modified to promote alternative fates? Can a mammalian taste bud be re-programmed during replacement to form an odontode or a keratinized tooth-like structuresimilar to the filiform papillae found in association with taste buds on mammalian tongues?[91]

To sum up, we argue that odontodes originated when two evolving CEGs (a neural crest-derived mesCEG and an ancestral epCEG; Figure 3) came together in embryological timeand space. This union galvanized an ‘odontode explosion’ during early vertebrate evolution,filling the oro-pharyngeal cavity and covering the epidermis of jawless vertebrates. We hopethis perspective will point the focus of future research on those signaling interactions thatspecify, maintain and delineate odontodes, their possible precursors, and their subsequentdescendants.



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AcknowledgmentsWe thank Brandon Milholland for his work on the genes expressed during cephalic lateral line development inMalawi cichlids. We also thank Moya Smith, Zerina Johanson, Ivan Horacek, Martin Kralovic and four anonymousreviewers for their comments on previous versions of the manuscript. This work was supported by grants awardedto JTS (NIH-R01DE019637) and RC (MSMT-0021620828; GACR-206/09/10007).

Glossary of Terms

Tooth a mineralized hard tissue unit consisting of attachment bony basalpad, dentine or similar dentinous tissue sometimes with a superficiallayer of enamel/enameloid formed from a single papilla present onlyin the oro-pharyngeal cavity, with a distinctive patterned oro-pharyngeal distribution with associated/connected replacementsdeveloping in advance of their requirement [1]

Denticle a mineralized structure, present on the dermal surface and within theoro-pharyngeal cavity of basal vertebrates (e.g. elasmobranchs),consisting of attachment bone, dentine sometimes with a superficiallayer of enameloid formed from a single papilla[1–3], with a random(non-patterned) distribution and unrelated replacements

Odontode all structures that comprise a mineralized hard tissue unit consistingof attachment bony basal pad, dentine or similar dentinous tissuesometimes with a superficial layer of enamel/enameloid formed froma single papilla; odontodes include both teeth and denticles[4,5]

Neural Crest A migratory multipotent embryonic progenitor cell population thatemerges from the dorsal neural tube to invade diverse regions of theembryo, giving rise to numerous derivatives in vertebrates includingneurons, glia, pigment cells, bone, cartilage and dentine

Gene RegulatoryNetwork (GRN)

A coordinated collection of genes that govern the time, position andrates at which other genes in the network are transcribed. A GRN isusually derived from data obtained through experimentalmanipulation in model organisms, and is often portrayed as a logicalwiring diagram [6,7]

Gene Co-expression Group(CEG)

genes expressed with spatial and temporal similarity, only suggestiveof GRN function; similar to synexpression groups [8]

Agnathan Jawless vertebrates, likely a paraphyletic group to the gnathostomes

Gnathostomes Vertebrates with opposable oral jaws

Oro-pharyngealcavity

the anterior opening of the mouth and the cavity leading to the gut

List of Abbreviations

BMP Bone morphogenetic protein family

FGF Fibroblast growth factor family

CEG Gene co-expression group

cLL Cephalic lateral line



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epCEG Epithelial placode gene co-expression group

GRN Gene regulatory network

mesCEG Mesenchymal gene co-expression group

ncGRN Neural crest gene regulatory network

oGRN Odontode gene regulatory network

tbCEG taste bud gene co-expression group

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Figure 1. Theories of odontode evolutionSchematic diagrams represent a generalised (hypothetical) early vertebrate/fish in lateral/sagittal view: A1: Outside-in theory; ectodermal tissue is hypothesized to have integrated(green arrow) into the oro-pharyngeal cavity (opc), leading to the evolution of oralodontodes and subsequently oral and pharyngeal teeth. A2: Modified outside-in theory;ectodermal tissue integrated (green arrow) into the endodermal oral cavity via the mouthopening (the anterior boundary of the endoderm and ectoderm) and the gill slits (gs) in earlyvertebrates to initiate/transfer dental competence (arrow) to the endoderm of the oro-pharyngeal cavity. The point is made that ectoderm must be in regional contact withendoderm for teeth to form. B: Inside-out theory; skin denticles and teeth are structuresforming independently from ectoderm and endoderm, respectively. This theory states thatteeth originated in the posterior pharyngeal endoderm of jawless vertebrates; a dentalcompetence that was co-opted anteriorly (red arrow) in concert with the evolution of oraljaws. This theory states that skin denticles did not grade into teeth. e, eye; n, nasal placode;opc, oro-pharyngeal cavity.



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Figure 2. The inside and out gene regulatory hypothesis for odontode evolutionA. Schematic diagram represents a generalised early vertebrate/fish in lateral/sagittal view:We propose that regardless of tissue origin (endoderm or ectoderm), the ingredients forodontode evolution, instigated by the appearence of the putative odontode gene regulatorynetwork (oGRN), involved the collaboration of two pre-existing gene co-expression groups:(i) the neural crest-derived ectomesenchymal co-expression group (mesCEG) and (ii) theepithelial co-expression group (epCEG), which operates within both the endoderm andectoderm (B). C: The evolution of both skin denticles and teeth were separate operations ofthe combination of epCEG and mesCEG in alternative locations, the epidermis and the oro-pharngeal cavity (opc). Within the opc, co-option of the oGRN potential was transfered tothe oral jaws during the transition from jawless (agnathans) to jawed vertebrates(gnathostomes).



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Figure 3. Epithelial transitions and innovative network consolidationA. a generalised epithelia from which a thickened epithelial placode initiates, B: The genesexpressed within this thickening can be described as the epithelial co-expression group(epCEG). From this thickened epithelial placode the epithelium can transition into a numberof structures: C: a taste bud, a similar sensory unit, is a superficial epithelial element possinga unique epithelial gene expression signature (tbCEG); D: a denticle and E: a tooth recruitthe underlying mesenchyme that contains the neural crest-derived cell population and the setof genes associated with the neural crest-derived ectomesenchyme (mesCEG). Note that thiscollection of genes is related to and influenced by the ncGRN. For a more complete list ofgenes that interact in the ncGRN, embryo-wide, see [69,70]. We propose the mesCEGcollaborated with the epCEG to provide the ingredients for the oGRN (see also Figure 2).Skin denticles and teeth are born from the odontode GRN as they are both odontodes bydefinition. The tooth itself houses a unique subset of genes (collectively the dental GRN).This coordinated gene network contains genes that are not shared with scales and thus weassume dermal denticles, highlighting their evolutionary and developmental separation. Thedivergence between members of the oGRN and dGRN reflects those genes only expressed inthe dentition versus those expressed across odontodes determined from expression duringteleost scale development; it remains to be tested whether these expression trends hold fordenticles of extant sharks and rays.



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Table 1Conserved and coordinated gene expression during the initiation stage of divergentepithelial-contributed structures

taste bud[102–104], tooth[34,47], gill raker[47], scale [NB, within this discussion we address the earlyevolution of denticles, of which expression data is as yet unavailable; this screen was performed on thedeveloping scales of Malawi cichlids, scales present on teleosts are not the same in structure or developmentas placoid scales (skin denticles) of chondrichthyans], and the cephalic lateral line (cLL). Bracketed genesrefer to differential gene expression among vertebrate groups. Expression data from the teleost (Cichlidae)cLL placode (Fraser, Milholland and Streelman) and scale (Fraser and Streelman) are currently unpublished.


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Author Manuscript NIH Public Access 1,*, Vladimir Soukup ... · However, did the first odontode appear within the evolving oro- pharyngeal cavity for food breakdown during the transition