pmc.ncbi.nlm.nih.gov

Molecular Genetics of Tooth Development

. Author manuscript; available in PMC: 2010 Oct 28.

Published in final edited form as: Curr Opin Genet Dev. 2009 Oct 28;19(5):504–510. doi: 10.1016/j.gde.2009.09.002

Abstract

Organogenesis depends upon a well-ordered series of inductive events involving coordination of molecular pathways that regulate the generation and patterning of specific cell types. Key questions in organogenesis involve the identification of the molecular mechanisms by which proteins interact to organize distinct pattern formation and cell fate determination. Tooth development is an excellent context for investigating this complex problem because of the wealth of information emerging from studies of model organisms and human mutations. Since there are no obvious sources of stem cells in adult human teeth, any attempt to create teeth de novo will likely require the re-programming of other cell types. Thus, the fundamental understanding of the control mechanisms responsible for normal tooth patterning in the embryo will help us understand cell fate specificity and may provide valuable information towards tooth organ regeneration.

Keywords: tooth, genetics, transgenic, mouse, molecular mechanisms

Introduction

Teeth, like all epithelial appendages, form via a sequential and reciprocal series of inductive signals transmitted between the epithelium and neural crest derived mesenchyme. Each tissue layer instructs the other to differentiate in a precisely determined manner leading to the formation of highly specialized structures, such as incisors, canines, premolars and molars. Each of these groups of teeth derives from different parts of the oral epithelium and, depending on the species, teeth can be formed from both endoderm and ectoderm or from ectoderm only [1, 2••].

Morphologically, tooth development commences with a thickening of the dental epithelium to form a structure known as the dental lamina (Figure 1). Within this band of thickened epithelium the cells start to proliferate and to invaginate in certain positions to form the placodes. After this fundamental step in development, further epithelial invagination and convolution form the bud, cap and bell stages of tooth morphogenesis (Figure 1). During these stages, the constant interplay of inductive signals between the epithelium and mesenchyme (i) gives rise to distinct anatomical and functional parts of the tooth and (ii) mediates the differentiation of the epithelium into enamel-secreting ameloblasts and that of the mesenchyme into dentin-secreting odontoblasts (Figure 1).

Figure 1.

Figure 1

Animal and human studies that employ the tools of contemporary molecular genetics have identified a number of genes that act at specific stages of tooth development and regulate its patterning and differentiation process (Figure 1; Tables 1–2; http://bite_it.helsinki.fi). The purpose of this review is to discuss in general terms some recent findings regarding genes and pathways that control tooth development and to provide new perspectives on the potential molecular mechanisms that coordinate the process of odontogenesis and tooth regeneration.

TABLE 1.

Abnormalities caused by mutations in transgenic mice affecting tooth formation

Gene Mutation Tooth Phenotype Reference
Msx1, Msx2 Double mutant Initiation stage arrest Bei and Maas (1998)
Dlx1, Dlx2 Double mutant Initiation stage arrest Thomas et al. (1997)
Fgf8 Fgf8flox Initiation stage arrest Trumpp et al. (1999)
Lhx6/Lhx7 Double mutant initiation stage arrest Grigoriou et al., (1998)
Pitx2 Null Initiation stage arrest Liu et al. (2003)
Gli2, Gli3 Double mutant Initiation stage arrest Hardcastle et al. (1998),
P63 Null Initiation stage arrest Yang et al. (1999)
Dkk1 K14 transgenic Initiation stage arrest Andl T et al. (2002)
Pax9 Null Bud stage arrest Peters et al. (1998)
Lef1 Null Bud stage arrest Van genderen et al. (1994)
Msx1 Null Bud stage arrest Satokata and Maas (1994)
Runx2 Null Bud stage arrest Aberg et al. (2004)
Barx1 Null Bud stage arrest Tucker et al. (1998)
Bmpr1a K14 transgenic Bud stage arrest Andl et al. (2004)
Fgfr2b Null Bud stage arrest De Moerlooze et al. (2000)
Shh K14 conditional KO Bud stage arrest Dassule et al. (2000)
Noggin K14 TG Bud stage arrest Plikus et al. (2005)
Activin βA Null Bud stage arrest, lack incisors and mandibular molars Matzuk et al. (1995)
Ctip2 Null Late bell stage defect Golonzhka et al. (2009)
Gli2 Null Abnormal maxillary incisor Hardcastle et al. (1998)
Gli3 Heterozygous Maxillary incisor development arrested as a rudimentery epithelium thickening Hardcastle et al. (1998), Mo et al. (1997)
Eda Tabby encode eda Small enamel knot Tucker et al.(2000)
Edar Downless Absent enamel knot, disorgonized enamel rope Headon and Overbeek (1999)
Fgf10 Null Smaller tooth germ, cervical loops of the incisors are hypoplastic Harada et al. (2002)
Wnt/β catenin K14 conditional KO Misshappen tooth bud, ectopic teeth Liu et al. (2008)
Ectodin/Sostdc1/wise Null Supernumerary teeth, enlarge enamel knot, abnormal cusp Kassai et al. (2005)
Apc K-14Cre;Apccko/cko Supernumerary teeth Kuraguchi et al. (2006)
Sp6 Null Supernumerary teeth Nakamura et al. (2008)
Lrp4 Null Supernumerary teeth Johnson et al. (2005)
IFT88/polaris Null Supernumerary teeth Liu et al., (2005)
Gas1 Null Supernumerary teeth Ohazama et al., (2009)
Osr2 Null Supernumerary teeth Zhang et al.(2009)
Sprouty2,4 Null Supernumerary teeth Klein et al. (2006)

TABLE 2.

Abnormalities caused by mutation in transgenic mice affecting tooth matrix deposition and root formation

Gene Mutation Tooth phenotype Reference
Enamel defect
Msx2 Null Enamel hypoplasia Satokata et al. (2000)
Lama3 Null Enamel hypoplasia Ryan et al. (1999)
Sp3 Null Enamel hypoplasia Bowman et al. (2000)
Sp6 Null Enamel hypoplasia Nakamura et al. (2008)
Smoothened K14 conditional KO Enamel hypoplasia Gritli-Linde et al. (2002)
Gdnf Null No enamel deVicente et al. (2002)
Periostin Null Incisor enamel defect Rios et al. (2005)
TGFB1 Dspp conditional KO Enamel hypoplasia Haruyama et al. (2006)
Eda K14 transgenic No enamel Mustonen et al. (2004)
Follistatin K14 transgenic No enamel Wang et al. (2004)
Follistatin Null Ectopic enamel Wang et al. (2004)
Wnt3 K14 transgenic No enamel Millar et al. (2003)
Amelx Null Enamel hypoplasia Gibson et al. (2001)
Ameloblastin Null No enamel Fukumoto et al. (2005)
Tbx1 Null Enamel free teeth Caton et al. (2009)
Enamelin Null Enamel hypoplasia/aplasia Hu et al. (2008)
Mmp20 Null Enamel hypoplasia Caterina et al. (2002)
Connexin 43 Dominant negative Enamel hypoplasia Dobrowolski et al. (2008)
Sprouty2,4 Spry2+/−, Spry4−/− Ectopic enamel Klein et al. (2008)
Periostin Null Thinner enamel layer, Rios et al. (2005)
Noggin K14 transgenic Abnormal ameloblast Plikus et al.(2005)
Dentin defect
Dspp Null Dentinogenesis Imperfecta Thyagarajan et al. (2001)
DMP1 Null Abnormal dentin tubule system Lu et al. (2007)
Msx2 Null Dentinogenesis imperfecta Aioub et al. (2007)
Sp6 Null Abnormal dentin stucture Nakamura et al. (2008)
Sp3 Null Dentin defect Bowman et al. (2000)
Noggin K14 transgenic Abnormal dentinoblast Plikus et al.(2005)
Root defect
Msx2 Null Root malformation Satokata et al. 2000
Shh Ptc mes Shorter root Nakatomi et al. (2006)
Nfi-c/CTF Null Lacking root Steele-perkins et al. (2003)
Sp6 Null Defect in root formation Nakamura et al. (2008)
Noggin K14 transgenic Failed to form multiple root Plikus et al.(2005)

Genes and pathways involved in regulation of tooth development

Four major signaling pathways and their inhibitors control tooth formation: a fine balance that determines number and patterning

The conserved signaling pathways of BMP, FGF, SHH and WNT ligands and their receptors constitute the key pathways that are used reiteratively during tooth development and mediate the epithelial–mesenchymal interactions [3, 4]. Over the past 15 years, studies using transgenic animals provided functional data showing that, in most cases, disruption of genes that are part of these signaling pathways results in severe aberrations of tooth development, such as complete tooth agenesis or arrest of tooth development at early stages of development (the lamina or bud stage of development), leading to anodontia (lack of teeth) [reviewed in 5, 6•, 7, 8•; Tables 1–2 and Figure 1]. For example, conditional inactivation of FGF8 in the dental epithelium results in arrest of tooth development at the lamina stage. Over-expression of BMPR1a in transgenic mice, or functional inactivation of FGFR2b or SHH results in arrest of tooth development at the bud stage [reviewed in 4, 5].

Recently, however, it was realized that the inhibitors of these signaling pathways also contribute to control tooth development. In most cases, when the inhibitors or mediators of these signaling pathways are perturbed, more teeth are formed with abnormal shape, ameloblast or odontoblast differentation defects and reduced matrix deposition [9, 10, 11, 12, 13•, 14••; reviewed in 8, Tables 1–2].

For example, loss of Ectodin leads to supernumerary teeth through inhibition of BMP signaling [10•]. Ectodysplasin (Eda), a WNT signaling mediator, when overexpressed can lead to supernumerary teeth [15, 16]. Apc (Adenomatous polyposis coli), another WNT modifier that organizes the complex that degrades β-catenin, results in multiple tooth buds when conditionally knocked out in the oral epithelium,. Consistently, when β-catenin is overexpressed results in supernumerary teeth. These results suggest that overexpression of the canonical WNT signaling, either through loss of function of its inhibitors or by overexpression of its effectors leads to supernumerary teeth [11, 17, 18]. The importance of the tooth-inductive potential of WNT signaling manipulation is further demonstrated by the recent discovery that WNT pathway activation, even postnatally, lead to formation of extra teeth [14••]. Moreover, a member of the low-density receptor-related protein family, Lrp4, that modulates and integrates both the BMP and the canonical WNT signalling by binding the secreted BMP antagonist protein Ectodin, when mutated in mice results in supernumerary incisors and molars as well as fused molars, a phenotype identical to that of Ectodin mouse mutant [19].

As in the case of BMP and WNT pathways, the mediators and/or inhibitors of the SHH and FGF signaling lead to supernumerary teeth, when mutated. Primary cilia mediate SHH signaling, since mutations in their protein components affect SHH activity. Mice mutant for a cilia intraflagellar transport (IFT) protein, IFT88/polaris, result in the formation of ectopic teeth, through increase of Shh activity in the toothless region of the embryonic jaw primordia, the diastema region [20, 21, 22••]. Consistently, upregulation of Shh activity in mice mutant for Gas1, a Shh protein antagonist, results in ectopic diastema teeth [22••]. Finally, inactivation of either Sprouty2 (Spry2) and/or Sprouty 4 (Spry4), the inhibitors of FGF signaling, leads to supernumerary teeth in the diastema [12, 13].

These studies demonstrate that tooth formation is the result of a tight control between networks of activators and inhibitors, and that any modification of these networks leads to abnormalities in either number or patterning. Interestingly, the transcription factors that mediate such signaling networks are indispensable for early and late tooth development as well. Genetic experiments where the function of transcription factors such as Msx1, 2, Dlx1, 2, 5, Runx2, Pax9, Pitx2, Lef1, Gli1, 2, 3, Lhx6, 7, 8, Prx1, 2 and others (http://bite-it.helsinki.fi) is eliminated in mice or humans results in most cases in an arrest of tooth development at the bud stage or before during the lamina stage, leading to anodontia [Tables 1–2; 5, 6•, 8•; Figure 1]. Exception to the rule is the case of Sp6, a zinc finger transcription factor known as Epfn. Sp6 null mice develop numerous teeth, up to 50 incisors and 8 molars, and that would be a surprise, if we didn’t know that Sp6 functions through upregulation of Lef1, a target, again, of WNT signaling, whose activation leads to extra teeth, as mentioned above [23].

Another transcription factor that leads to supernumerary teeth upon mutation is Odd-skipped related −2 (Osr2) [24••]. The study by Zhang et al. regarding the role of Osr2 transcription factor in tooth development stands alone, since most of the mouse mutants that develop extra buds/teeth do so in the toothless diastema region along the already formed single row of teeth. In contrast, Osr2 deletion in mice leads to supernumerary teeth lingual to their molars, thus forming a second row of molars, through up-regulation and expansion of the odontogenic field that is driven by the BMP4-Msx1-BMP4 pathway in the mesenchyme [25]. Thus, normally, Osr2 suppresses this pathway along the buccolingual axis to restrict molar development to one tooth row in mice [24••].

Complex networks of signaling pathways and the control of tooth diversity in evolution

The studies mentioned above indicate the importance of keeping a fine balance between signaling ligands, their receptors, inhibitors and transcription factors in regulating all aspects of tooth development, including the patterning, the size, the number and the shape. Since perturbations of these pathways lead to such fundamental changes in patterning and number, one could hypothesize that evolution favored certain pathways versus others in promoting certain changes in the dentition of vertebrate species.

For example, many non-mammalian vertebrates, such as fish or reptiles, replace their teeth throughout their life, have multi-rowed dentition and their teeth are all of simple shape, while mammalian vertebrates develop teeth in a single row, replace their teeth once or not at all, and the teeth acquire different shapes and forms such as incisors, canines, pre-molars and molars [1, 26, 27]. Mice are examples of mammalian vertebrates that possess molars and incisors only, they are monophyodonts (one set of teeth) and they develop their teeth in a single raw. The ancestors of mice, however, the Glires, a clade including rodents and lagomorphs, possessed premolars and canines similar to the dentition observed in non-rodent species [28]. Interestingly, some rodents, such as squirrels and guinea pigs, still have premolar teeth, suggesting that the genetic information specifying premolar and canine tooth shapes or tooth replacement processes is still in place.

The phenotypes of numerous knock out and transgenic mice that form either additional teeth in the diastema region, a region where normally premolars and canines would have exist, or multiple de novo teeth, or multi-rowed dentition just by perturbing a signaling pathway, support such a hypothesis (Tables 1–2; this review).

Stem cells in teeth and their potential to be regenerated

Despite the progress made from genetic studies described above, the processes involved in the formation of extra teeth and tooth replacement are still not known. Some studies suggest that Pitx2 and Bmp4 are key molecules associated with continuous tooth replacement in fish [26]. Mammals, such as mice, that do not replace their teeth, form de novo teeth when the WNT signaling is over-expressed [11, 14••, 17, 18]. Could any of these pathways be the key to regenerate teeth in humans? Can we use the pathway network knowledge to drive stem cell differentiation processes towards de novo tooth formation?

Currently, efforts towards that goal are concentrated in an attempt to discover adult stem cells in human or mouse teeth. Mesenchymal stem cells have been identified in adult human teeth in the dental pulp (DPSCs) and in the dental follicle (DFSCs) [29, 30]. These cells have stem cell properties, can be cultured as stem cells in vitro, can form colonies and differentiate in vivo into odontoblasts, cementoblasts and periodontal ligament cells [31]. Dental epithelial cells, from the quiescent Epithelial Cell Rests of Malassez (ERM)-the only dental epithelium remaining after root formation, located within the periodontal ligament (PDL)-were isolated from pigs and differentiated into ameloblast-like cells producing enamel in vivo, when co-seeded with dental pulp cells [32]. Using the continuously growing incisor of the mouse as a model for the study of adult epithelial stem cells, researchers have shown that label-retaining cells were localized in the epithelially derived cells of the cervical loop, and this population of cells has been proposed to constitute the mouse incisor stem cell niche [33]. Further studies indicated that members of the FGF family of ligands, namely FGF3 and FGF10, derived from mesenchyme, promote the proliferation and survival of the incisor epithelial stem cell niche [33, 34, 35••]. Consistently, FGF10 is downregulated in teeth that do not grow continuously, such as the mouse molar, while the addition of FGF10 to cultured mouse molars promotes the maintenance of their cervical loops [36].

Although these studies have provided some insight on potential sources of tooth stem cells in pigs and mice, the fact remains that adult human teeth do not grow continuously and no human stem cell niches have yet been identified. The epithelial cell rests of Malassez (the only remaining epithelial cells after the tooth completes its development), the dental pulp and dental follicle stem cells that have been isolated from humans are promising, but their stemness is not yet well established and, more importantly, there is no evidence yet that they are capable to direct tooth morphogenesis.

Future Directions: Reprogramming of adult differentiated cells and the search for the unique molecular identity of teeth

Recent advances in adult cell reprogramming through the creation of induced pluripotent stem (iPS) cell lines from adult differentiated cells offer the possibility to produce pluripotent stem cells from patient’s own tissue [37•, 38]. IPS cells are created by forced expression of defined transcription factors as Oct4, Sox2, cmyc, and Klf4, which have been shown to induce pluripotency in somatic fibroblast cells [39••]. In another study, iPS cells were generated from human fibroblasts using Oct4, Sox2, Nanog, and Lin28 [40]. Although the four reprogramming factors were different in these two studies, all of them were transferred into the cells by means of retrovirus gene transfer, which holds some risk to cause insertion mutations. In addition, since some of the reprogramming factors are oncogenes as well, the risk of tumor induction is another potential limitation to be considered. A recent breakthrough study by the group of Doug Melton succeeded to directly reprogram pancreatic exocrine cells to insulin producing beta cells [41••]. This method is more advanced to the reprogramming of any adult differentiated cells to iPS cells, because the pancreatic exocrine cells share a common genomic and epigenomic identity with those of insulin producing beta cells. The latter approaches could be promising and suggest that tooth-specific cell types, such as ameloblasts or dental follicle cells, with matrix producing capability could be produced through reprogramming of adult cell types. Whether reprogramming of adult cells to iPS and then programming of iPS can be used to generate, instead of specific cell types, a rather complex three-dimensional organ like the tooth, is not yet known.

The tooth is a complex organ and its development a process controlled by a sequence of cellular and molecular networks that act at particular places and times to guide pluripotent cells to restricted dental cell fates. The mechanisms that control and determine the history of the cells so that the differentiation program is properly executed during embryonic development are not known. Despite the fact that genetics and epistasis analysis have led to the discovery of numerous genes and pathways involved during different stages of tooth development, the same genes are required for the development of other tissues, especially that of other ectodermal organs such as hairs, nails and glands [Figure 1 and Tables 1–2]. In addition, perturbations of these genes affect not only tooth development but, in most cases, the development of other ectodermal organs, thus leaving open the obvious question of cell fate specificity [8, 42].

What it is known, however, is that transcription factors control cell fate through a selective regulation of target genes, and that the target gene specificity is achieved through context-dependent selective protein interactions. Recent studies suggest that in early tooth morphogenesis, a network of transcription factors operate in the dental mesenchyme to regulate a specific transcriptional output and that their combinatorial action, along with their target specificity is further modified by epigenetic mechanisms, such as sumoylation (Bei unpublished). The need of such a comprehensive analysis at the molecular level, along with extensive whole-genome data sets -including ChIP-chip and ChIP-Seq of multiple transcription factors-, maps of epigenetic states, expression profiling of genetically manipulated cells, would help determine the molecular identity of the tooth and permit controlling of the iPS programming towards the generation of de novo teeth.

Acknowledgments

This work was supported by grants from the NIH (RO3 DE 018415; RO1 DE 19226), Harvard Skin Disease Research Center (Pilot Fund Award) and Harvard Medical School (Milton Fund Award) to MB. We thank Dr. Intan Ruspita for her help in preparing the tables and figure.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References and recommended reading

Papers of particular interest, some published within the period of review, have been highlighted as:

• of special interest

•• of outstanding interest

  • 1.Smith MM. Vertebrate dentitions at the origin of jaws: when and how pattern evolved. Evol Dev. 2003;5:394–413. doi: 10.1046/j.1525-142x.2003.03047.x. [DOI] [PubMed] [Google Scholar]
  • 2••.Soukup V, Epperlein H, Horacek I, Cerny R. Dual epithelial origin of vertebrate oral teeth. Nature. 2008;455:795–796. doi: 10.1038/nature07304. Using transgenic axolotls with a combination of fate-mapping approaches, the authors provided evidence for oral teeth derived from both the ectoderm and endoderm and, moreover, they demonstrated teeth with a mixed ecto/endodermal origin. [DOI] [PubMed] [Google Scholar]
  • 3.Mikkola ML. Genetic basis of skin appendage development. Semin Cell Dev Biol. 2007;18:225–236. doi: 10.1016/j.semcdb.2007.01.007. [DOI] [PubMed] [Google Scholar]
  • 4.Thesleff I. Epithelial-mesenchymal signalling regulating tooth morphogenesis. J Cell Sci. 2003;116:1647–1648. doi: 10.1242/jcs.00410. [DOI] [PubMed] [Google Scholar]
  • 5.Fleischmannova J, Matalova E, Tucker AS, Sharpe PT. Mouse models of tooth abnormalities. Eur J Oral Sci. 2008;116:1–10. doi: 10.1111/j.1600-0722.2007.00504.x. [DOI] [PubMed] [Google Scholar]
  • 6•.Bei M. Molecular genetics of ameloblast cell lineage. Journal Exp Zool (Mol Dev Evol) 312B. 2009;5:437–444. doi: 10.1002/jez.b.21261. In this review the author discusses the role of genes that play definitive role on the determination of ameloblast cell fate and life cycle based on studies in transgenic animals. Mutations in both mouse and humans reveal the involvement of several classes of genes in ameloblast life cycle and its function, a process that emerges as a model for elucidating the molecular regulatory cascades that operate in other developmental systems as well. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Caton J, Tucker AS. Current knowledge of tooth development: patterning and mineralization of the murine dentition. J Anat. 2009;219:502–515. doi: 10.1111/j.1469-7580.2008.01014.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8•.Tummers M, Thesleff I. The importance of signal pathway modulation in all aspects of tooth development. Journal Exp Zool (Mol Dev Evol) 312B. 2009;5:309–319. doi: 10.1002/jez.b.21280. In this review the authors discuss the complexity of the regulatory network involved in all facets of tooth development. This complexity leads to the availability of numerous developmental solutions to the same problem, all of which are accomplished by regulatory tinkering. We conclude that the complexity and nature of the signalling network probably facilitated the change of tooth shapes and patterns during evolution. [DOI] [PubMed] [Google Scholar]
  • 9.Wang XP, Suomalainen M, Jorgez CJ, Matzuk MM, Werner S, Thesleff I. Follistatin regulates enamel patterning in mouse incisors by asymmetrically inhibiting BMP signaling and ameloblast differentiation. Dev Cell. 2004;7:719–30. doi: 10.1016/j.devcel.2004.09.012. [DOI] [PubMed] [Google Scholar]
  • 10.Kassai Y, Munne P, Hotta Y, et al. Regulation of mammalian tooth cusp patterning by ectodin. Science. 2005;309:2067–2070. doi: 10.1126/science.1116848. [DOI] [PubMed] [Google Scholar]
  • 11.Kuraguchi M, Wang XP, Bronson RT, Rothenberg R, Ohene-Baah NY, Lund JJ, Kucherlapati M, Maas RL, Kucherlapati R. Adenomatous polyposis coli (APC) is required for normal development of skin and thymus. PLoS Genet. 2006;2:146. doi: 10.1371/journal.pgen.0020146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Klein OD, Minowada G, Peterkova R, et al. Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial–mesenchymal FGF signaling. Dev Cell. 2006;11:181–190. doi: 10.1016/j.devcel.2006.05.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13•.Klein OD, Lyons DB, Balooch G, et al. An FGF signaling loop sustains the generation of differentiated progeny from stem cells in mouse incisors. Development. 2008;135:377–385. doi: 10.1242/dev.015081. The authors show that sprouty genes, which encode antagonists of receptor tyrosine kinase signaling, function to ensure that enamel-producing ameloblasts are generated on only one side of the tooth by inhibiting the formation of ectopic ameloblasts from self-renewing stem cells, and that they do so by preventing the establishment of an epithelial-mesenchymal FGF signaling loop. These data reveal that the generation of differentiated progeny from a particular stem cell population can be differently regulated in the embryo and adult. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14••.Wang XP, O’Conell DJ, Lund J, Saadi I, Kuraguchi M, Turbe-Doan A, Cavallesco R, Kim H, Park PJ, Harada H, Kucherlapati R, Maas RL. Apc inhibition of Wnt signaling regulates supernumerary tooth formation during embryogenesis and throughout adulthood. Development. 2009;136:1939–1949. doi: 10.1242/dev.033803. In this study the authors demonstrate that adult dental tissues can form new teeth in response to either epithelial Apc loss-of-function or beta-catenin activation, and that the effect of Apc deficiency is mediated by beta-catenin. The formation of supernumerary teeth via Apc loss-of-function is non-cell-autonomous. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Mustonen T, Pispa J, Mikkola ML, Pummila M, Kangas AT, Pakkasjarvi L, Jaatinen R, Thesleff I. Stimulation of ectodermal organ development by Ectodysplasin-A1. Dev Biol. 2003;259:123–136. doi: 10.1016/s0012-1606(03)00157-x. [DOI] [PubMed] [Google Scholar]
  • 16.Pispa J, Mustonen T, Mikkola ML, Kangas AT, Koppinen P, Lukinmaa PL, Jernvall J, Thesleff I. Tooth patterning and enamel formation can be manipulated by misexpression of TNF receptor Edar. Dev Dyn. 2004;231:432–440. doi: 10.1002/dvdy.20138. [DOI] [PubMed] [Google Scholar]
  • 17.Jarvinen E, Salazar-Ciudad I, Birchmeier W, Taketo MM, Jernvall J, Thesleff I. Continuous tooth generation in mouse is induced by activated epithelial Wnt. Proc Natl Acad Sci USA. 2006;103:18627–18632. doi: 10.1073/pnas.0607289103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Liu F, Chu EY, Watt B, et al. Wnt/beta-catenin signaling directs multiple stages of tooth morphogenesis. Dev Biol. 2008;313:210–224. doi: 10.1016/j.ydbio.2007.10.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ohazama A, Johnson EB, Ota MS, Choi HJ, Porntaveetus T, Oommen S, Itoh N, Eto K, Gritli-Linde A, Herz J, et al. Lrp4 modulates extracellular integration of cell signaling pathways in development. PLos One. 2008;3:4092. doi: 10.1371/journal.pone.0004092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Liu A, Wang B, Niswander LA. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development. 2005;132:3103–3111. doi: 10.1242/dev.01894. [DOI] [PubMed] [Google Scholar]
  • 21.Zhang Q, Murcia NS, Chittenden LR, Richards WG, Michaud EJ, Woychik RP, Yoder BK. Loss of the Tg737 protein results in skeletal patterning defects. Dev Dyn. 2003;227:78–90. doi: 10.1002/dvdy.10289. [DOI] [PubMed] [Google Scholar]
  • 22••.Ohazama A, Haycraft CJ, Seppala M, Blackburn J, Ghafoor S, Cobourne M, Martinelli MC, Fan CM, Peterkova R, Lesot H, Yoder BK, Sharpe PT. Primary cilia regulate Shh activity in the control of molar tooth number. Development. 2009;136:897–903. doi: 10.1242/dev.027979. In this study the authors show that in mice mutant for a cilia intraflagellar transport (IFT) protein, IFT88/polaris, Shh activity is increased in the toothless diastema mesenchyme of the embryonic jaw primordia. This results in the formation of ectopic teeth in the diastema, mesial to the first molars. Interestingly, the ectopic teeth adopt a size and shape characteristic of premolars, a tooth type that was lost in mice around 50–100 million years ago. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Nakamura T, deVega S, Fukumoto S, Jimenez L, Unda F, Yamada Y. Transcription factor epiprofin is essential for tooth morphogenesis by regulating epithelial cell fate and tooth number. J Biol Chem. 2008;283:4825–4833. doi: 10.1074/jbc.M708388200. [DOI] [PubMed] [Google Scholar]
  • 24••.Zhang Z, Lan Y, Chai Y, Jiang R. Antagonistic actions of Msx1 and Osr2 pattern mammalian teeth into a single row. Science. 2009;323:1232–1234. doi: 10.1126/science.1167418. In this study the authors show that mice lacking the transcription factor odd-skipped related-2 (Osr2) develop supernumerary teeth lingual to their molars because of expansion of the odontogenic field. Osr2 was expressed in a lingual-to-buccal gradient and restricted expression of bone morphogenetic protein 4 (Bmp4), an essential odontogenic signal in the developing tooth mesenchyme. Expansion of the odontogenic field in Osr2-deficient mice required Msx1, a feedback activator of Bmp4 expression. These findings suggest that the Bmp4-Msx1 pathway propagates mesenchymal activation for sequential tooth induction and that spatial modulation of this pathway provides a mechanism for patterning vertebrate dentition. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Bei M, Kratochwil K, Maas RL. BMP4 rescues a non-cell autonomous function of Msx1 in tooth development. Development. 2000;127:4711–4718. doi: 10.1242/dev.127.21.4711. [DOI] [PubMed] [Google Scholar]
  • 26.Fraser GJ, Berkovitz BK, Graham A, Smith MM. Gene deployment for tooth replacement in the rainbow trout (Oncorhynchus mykiss): a developmental model for evolution of the osteichthyan dentition. Evol Dev. 2006;8:446–457. doi: 10.1111/j.1525-142X.2006.00118.x. [DOI] [PubMed] [Google Scholar]
  • 27.Fraser GJ, Bloomquist RF, Streelman JT. A periodic pattern generator for dental diversity. Bmc Biology. 2008;6:32. doi: 10.1186/1741-7007-6-32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Yamanaka A, Yasui K, Sonomura T, Uemura M. Development of heterodont dentition in house shrew (Suncus murinus) Eur J Oral Sci. 2007;115:4334–4340. doi: 10.1111/j.1600-0722.2007.00499.x. [DOI] [PubMed] [Google Scholar]
  • 29.Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA. 2000;97:13625–13630. doi: 10.1073/pnas.240309797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, Young M, Robey PG, Wang CY, Shi ST. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet. 2004;364:149–155. doi: 10.1016/S0140-6736(04)16627-0. [DOI] [PubMed] [Google Scholar]
  • 31.Yao S, Pan F, Prpic V, Wise G. Differentiation of stem cells in the dental follicle. J Dent Res. 2008;87:767–771. doi: 10.1177/154405910808700801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Shinmura Y, Tsuchiya S, Hata K, Honda MJ. Quiescent epithelial cell rests of Malassez can differentiate into ameloblast-like cells. J Cell Physiol. 2008;217:728–38. doi: 10.1002/jcp.21546. [DOI] [PubMed] [Google Scholar]
  • 33.Harada H, Kettunen P, Jung HS, Mustonen T, Wang YA, Thesleff I. Localization of putative stem cells in dental epithelium and their association with notch and FGF signaling. J Cell Biol. 1999;147:105–120. doi: 10.1083/jcb.147.1.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Harada H, Toyono T, Toyoshima K, Yamasak M, Itoh N, Kato S, Sekine K, Ohuchi H. FGF10 maintains stem cell compartment in developing mouse incisors. Development. 2002;129:1533–1541. doi: 10.1242/dev.129.6.1533. [DOI] [PubMed] [Google Scholar]
  • 35••.Wang X, Suomalainen M, Felszeghy S, Zelarayan LC, Alonso MT, Plikus MV, Maas RL, Chuong C, Schimmang T, Thesleff I. An integrated gene regulatory network controls stem cell proliferation in teeth. Plos Biology. 2007;5:1324–1333. doi: 10.1371/journal.pbio.0050159. In this study the authors show that spatially restricted and balanced effects of BMP, FGF and Activin signaling networks can regulate stem cell proliferation in the niche and account for asymmetric organogenesis. They also demonstrate that subtle variations in this or related regulatory networks may explain the different regenerative capacities of various organs and animal species. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Yokohama-Tamaki T, Ohshima H, Fujiwara N, Takada Y, Ichimori Y, Wakisaka S, Ohuchi H, Harada H. Cessation of Fgf10 signaling, resulting in a defective dental epithelial stem cell compartment, leads to the transition from crown to root formation. Development. 2006;133:1359–1366. doi: 10.1242/dev.02307. [DOI] [PubMed] [Google Scholar]
  • 37•.Nishikawa S, Goldstein RA, Nierras CR. The promise of human induced pluripotent stem cells for research and therapy. Nat Rev Mol Cell Biol. 2008;9:725–729. doi: 10.1038/nrm2466. In this review the authors discuss the possibility to generate induced pluripotent stem (iPS) cells from human somatic cells that have been reprogrammed to a pluripotent state. They also discuss how iPS can serve as a research tool, how iPS-cell technology provides opportunities to study normal development and to understand reprogramming and how iPS cells can have an immediate impact as models for human diseases, including cancer. [DOI] [PubMed] [Google Scholar]
  • 38.Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, Vassena R, Bilic J, Pekarik V, Tiscornia G, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol. 2008;26:1276–1284. doi: 10.1038/nbt.1503. [DOI] [PubMed] [Google Scholar]
  • 39.Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–676. doi: 10.1016/j.cell.2006.07.024. [DOI] [PubMed] [Google Scholar]
  • 40.Yu J, Vodyanik M, Smuga-Otto K, Antosiewicz-Bourget J, Frane J, Tian S, Nie J, Jonsdottir G, Ruotti V, Stewart R, Slukvin I, Thomson J. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–1920. doi: 10.1126/science.1151526. [DOI] [PubMed] [Google Scholar]
  • 41••.Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta cells. Nature. 2008;455:627–632. doi: 10.1038/nature07314. Using a strategy of re-expressing key developmental regulators in vivo, the authors identified a combination of the three transcription factors Ngn3 (also known as Neurog3, Pdx1 and Mafa that reprograms differentiated pancreatic exocrine cells from adult mice into cells that closely resemble beta-cells. The induced beta-cells are indistinguishable from endogenous islet beta-cells in size, shape and ultrastructure. They express genes essential for beta-cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provided an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Duverger O, Morasso MI. Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals. J Cell Physiol. 2008;216:337–346. doi: 10.1002/jcp.21491. [DOI] [PMC free article] [PubMed] [Google Scholar]