Intra-epithelial Requirement of Canonical Wnt Signaling for Tooth Morphogenesis

Zhu, Xiaojing; Zhao, Pan; Liu, YuDong; Zhang, XiaoYun; Fu, Jiang; Hou, Yu; Qiu, Mengsheng; Chen, Yiping; Hsu, Wei-Hsuan; Zhang, Zunyi

doi:10.1074/jbc.m113.462473

Cited by 51 publications

(62 citation statements)

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“…These Wnt ligands appear to act in both intra-and intertissue manners to regulate tooth development. Epithelial deletion of Catnb (Ctnnb1 -Mouse Genome Informatics), the gene encoding β-catenin, or Gpr177 (Wls -Mouse Genome Informatics), the product of which is required for secretion of Wnts, leads to an arrest of tooth development at the bud or early cap stage (Liu et al, 2008;Zhu et al, 2013). A similar developmental defect was also observed in mice lacking Catnb in the dental mesenchyme .…”

Section: Introductionmentioning

confidence: 79%

“…Elevated β-catenin signaling in the dental mesenchyme is detrimental to normal odontogenesis Multiple Wnt ligands are expressed in the dental epithelium of the developing tooth and have been demonstrated to act in an intra-4381 RESEARCH ARTICLE FGF sustains odontogenic fate epithelial manner to regulate early tooth development (Zhu et al, 2013). These epithelially expressed Wnts also act on dental mesenchyme and form a Wnt-BMP feedback circuit with mesenchymally expressed BMP4 to mediate epithelialmesenchymal interactions during early tooth development (O'Connell et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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FGF signaling sustains the odontogenic fate of dental mesenchyme by suppressing β-catenin signaling

Liu

Sun

et al. 2013

Development

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SUMMARYOdontoblasts and osteoblasts develop from multipotent craniofacial neural crest cells during tooth and jawbone development, but the mechanisms that specify and sustain their respective fates remain largely unknown. In this study we used early mouse molar and incisor tooth germs that possess distinct tooth-forming capability after dissociation and reaggregation in vitro to investigate the mechanism that sustains odontogenic fate of dental mesenchyme during tooth development. We found that after dissociation and reaggregation, incisor, but not molar, mesenchyme exhibits a strong osteogenic potency associated with robustly elevated β-catenin signaling activity in a cell-autonomous manner, leading to failed tooth formation in the reaggregates. Application of FGF3 to incisor reaggregates inhibits β-catenin signaling activity and rescues tooth formation. The lack of FGF retention on the cell surface of incisor mesenchyme appears to account for the differential osteogenic potency between incisor and molar, which can be further attributed to the differential expression of syndecan 1 and NDST genes. We further demonstrate that FGF signaling inhibits intracellular β-catenin signaling by activating the PI3K/Akt pathway to regulate the subcellular localization of active GSK3β in dental mesenchymal cells. Our results reveal a novel function for FGF signaling in ensuring the proper fate of dental mesenchyme by regulating β-catenin signaling activity during tooth development.

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Section: Introductionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

FGF signaling sustains the odontogenic fate of dental mesenchyme by suppressing β-catenin signaling

Liu

Sun

et al. 2013

Development

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“…Since numerous Wnt family members such as Wnt3, Wnt4, Wnt6, and Wnt10b are expressed in the dental epithelium and Wnt readouts are active in the dental mesenchyme, Wnt ligands may be inductive signals for odontoblast differentiation (Chen et al 2009). However, Zhu et al (2013) recently reported that the dental mesenchyme retains its own odontogenic program despite epithelial-specific ablation of Wls. In this experiment, all secreted Wnts from the inner enamel epithelium do not get synthesized, and thus paracrine signaling by Wnts is not required for odontoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Since the secretion of Wnt proteins is blocked by inactivation of Wls (Bartscherer et al 2006), conditional depletion of Wls has been extensively used to investigate the role of Wnt proteins in a variety of tissues, including brain, hair follicle, taste bud, and osteoblasts (Fu et al 2011;Zhong et al 2012;Myung et al 2013;Wan et al 2013;Zhu et al 2014). Recently, Zhu et al (2013) reported that tooth morphogenesis is arrested in tissue-specific ablation of Wls in the dental epithelium. Furthermore, disruption of Wls in osteocalcin (Ocn or bone gamma carboxyglutamate protein, Bglap) expressing cells leads to various tooth defects such as significant increase of dentin volume and density in upper incisors, idiopathic root resorption, and wider periodontal ligament space (Lim et al 2014a(Lim et al , 2014b(Lim et al , 2014c.…”

Section: Research-article2015mentioning

confidence: 99%

Wntless Regulates Dentin Apposition and Root Elongation in the Mandibular Molar

Bae

Kim

et al. 2015

J Dent Res

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Wnt signaling plays an essential role in the dental epithelium and mesenchyme during tooth morphogenesis. However, it remains unclear if Wnt ligands, produced from dental mesenchyme, are necessary for odontoblast differentiation and dentin formation. Here, we show that odontoblast-specific disruption of Wntless (Wls), a chaperon protein that regulates Wnt sorting and secretion, leads to severe defects in dentin formation and root elongation. Dentin thickness decreased remarkably and pulp chambers enlarged in the mandibular molars of OC-Cre;Wls CO/CO mice. Although the initial odontoblast differentiation was normal in the mutant crown, odontoblasts became cuboidal and dentin thickness was reduced. In immunohistochemistry, Wnt10a, β-catenin, type I collagen, and dentin sialoprotein were significantly down-regulated in the odontoblasts of mutant crown. In addition, roots were short and root canals were widened. Cell proliferation was reduced in the developing root apex of mutant molars. Furthermore, Wnt10a and Axin2 expression was remarkably decreased in the odontoblasts of mutant roots. Deletion of the Wls gene in odontoblasts appears to reduce canonical Wnt activity, leading to inhibition of odontoblast maturation and root elongation.

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“…Although most Wnt family members are expressed in the dental epithelium during early tooth morphogenesis, some Wnts, such as Wnt5a and Wnt10a, as well as Wnt signaling mediators, Axin2 and Lef-1, are expressed in developing odontoblasts [10][11][12][13] . Zhu et al 14) reported that tooth morphogenesis is arrested in tissuespecific ablation of Wls in the dental epithelium. We recently found that tissue-specific inactivation or constitutive stabilization of β-catenin (β-Cat) leads to disrupted odontoblast differentiation in roots or excessive dentin formation, respectively 15,16) .…”

Section: Introductionmentioning

confidence: 99%

The Role of Autonomous Wntless in Odontoblastic Differentiation of Mouse Dental Pulp Cells

Choi¹,

Kim²,

Ko³

et al. 2016

Journal of Korean Dental Science

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ORIGINAL ARTICLEPurpose: Wnt signaling plays an essential role in the dental epithelium and mesenchyme during tooth morphogenesis. Deletion of the Wntless (Wls) gene in odontoblasts appears to reduce canonical Wnt activity, leading to inhibition of odontoblast maturation. However, it remains unclear if autonomous Wnt ligands are necessary for differentiation of dental pulp cells into odontoblast-like cells to induce reparative dentinogenesis, one of well-known feature of pulp repair to form tertiary dentin. Materials and Methods:To analyze the autonomous role of Wls for differentiation of dental pulp cells into odontoblast-like cells, we used primary dental pulp cells from unerupted molars of Wls-floxed allele mouse after infection with adenovirus for Cre recombinase expression to knockout the floxed Wls gene or control GFP expression. The differentiation of dental pulp cells into odontoblast-like cells was analyzed by quantitative real-time polymerase chain reaction.Result: Proliferation rate was significantly decreased in dental pulp cells with Cre expression for Wls knockout. The expression levels of Osterix (Osx), runt-related transcription factor 2 (Runx2), and nuclear factor I-C (Nfic) were all significantly decreased by 0.3-fold, 0.2-fold, and 0.3-fold respectively in dental pulp cells with Wls knockout. In addition, the expression levels of Bsp, Col1a1, Opn, and Alpl were significantly decreased by 0.7-fold, 0.3-fold, 0.8-fold, and 0.6-fold respectively in dental pulp cells with Wls knockout.Conclusion: Wnt ligands produced autonomously are necessary for proper proliferation and odontoblastic differentiation of mouse dental pulp cells toward further tertiary dentinogenesis.

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Intra-epithelial Requirement of Canonical Wnt Signaling for Tooth Morphogenesis

Cited by 51 publications

References 50 publications

FGF signaling sustains the odontogenic fate of dental mesenchyme by suppressing β-catenin signaling

FGF signaling sustains the odontogenic fate of dental mesenchyme by suppressing β-catenin signaling

Wntless Regulates Dentin Apposition and Root Elongation in the Mandibular Molar

The Role of Autonomous Wntless in Odontoblastic Differentiation of Mouse Dental Pulp Cells

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