Wnt/β-catenin signaling, which is activated in odontomas, reduces Sema3A expression to regulate odontogenic epithelial cell proliferation and tooth germ development
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ABSTRACT:
PROVIDER: PRJNA480017 | ENA |
REPOSITORIES: ENA
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Project description:Odontomas are classified as odontogenic benign tumors, which show disorganized dental mineralized hard tissue formation in the jaw, but mechanisms in the induction of odontomas remain to be clarified. Odontomas are also thought to be developmental anomalies of tooth germ, which frequently occur in patients with familial adenomatous polyposis (FAP) involving activation of Wnt/b-catenin signaling. However, the roles of Wnt/b-catenin signaling in odontomas or odontogenic cells remain to be clarified. The current study was conducted to investigate the expression of b-catenin in odontomas and the function of Wnt/b-catenin signaling in odontogenic epithelial cells and tooth germ development. b-catenin frequently accumulated in the nucleus and/or cellular cytoplasm of remaining odontogenic epithelial cells in human odontoma specimens, immunohistochemically. Activation of Wnt/b-catenin signaling inhibited odontogenic epithelial cell proliferation and mouse tooth germ development, while inducing epithelial bud formation in the novel developed epithelial tooth bud culture system derived from mouse tooth germ. We identified Semaphorin 3A (Sema3A) as a downstream molecule of Wnt/b-catenin signaling using DNA microarray analysis and showed that Wnt/b-catenin signaling-dependent reduction of Sema3A expression resulted in suppression of odontogenic epithelial cell proliferation. Novel developed epithelial tooth bud culture system revealed that Sema3A expression is required in epithelial budding morphogenesis. These results suggest that Wnt/b-catenin signaling negatively regulates odontogenic epithelial cell proliferation and tooth germ development through decreased-Sema3A expression, and aberrant activation of Wnt/b-catenin signaling may be associated with the formation of odontomas.
2019-03-20 | GSE116739 | GEO
Project description:During embryonic organogenesis, the odontogenic potential resides in dental mesenchyme from the bud stage until birth. Mouse dental mesenchymal cells (mDMCs) isolated from the inductive dental mesenchyme of developing molars are frequently used in the context of tooth development and regeneration. cultured mDMCs could retain the odontogenic potential for 24 h with a ratio of 60% for tooth formation, but mDMCs were incapable of supporting tooth formation after more than 24 h in culture. To reveal the underlying mechanism of the impairment of odontogenic potential, we generated gene expression profiles from mDMCs in culture using RNA-seq.
2016-10-31 | GSE78228 | GEO
Project description: Not available
| S-EPMC6414619 | biostudies-literature
Project description:Previous studies have suggested that Bmp4 is a key Msx1-dependent mesenchymal odontogenic signal for driving tooth morphogenesis through the bud-to-cap transition. Whereas the bud stage tooth developmental arrest in Msx1-/- mutant mice was accompanied by reduction in mesenchymal Bmp4 mRNA expression, we show that depleting functional Bmp4 mRNAs in the tooth mesenchyme, through neural crest-specific gene inactivation in Bmp4f/f;Wnt1Cre mice, caused mandibular molar developmental arrest at the bud stage but allowed maxillary molars and incisors to develop to mineralized teeth. We show that the Wnt inhibitors Dkk2 and Wif1 were much more abundantly expressed in the mandibular than maxillary molar mesenchyme in wildtype embryos and that Dkk2 expression was significantly unregulated in the tooth mesenchyme in Bmp4f/f;Wnt1Cre embryos. In addition, expression of Osr2, which encodes a zinc finger protein that antagonizes Msx1-mediated activation of odontogenic mesenchyme, is significantly upregulated in the molar mesenchyme in Bmp4f/f;Wnt1Cre embryos. Msx1 heterozygosity enhanced maxillary molar developmental defects whereas Osr2 heterozygosity rescued mandibular first molar morphogenesis in Bmp4f/f;Wnt1Cre mice. Moreover, in contrast to complete lack of supernumerary tooth initiation in Msx1-/-Osr2-/- mutant mice, Osr2-/-Bmp4f/f;Wnt1Cre compound mutant mice exhibit formation and subsequent arrest of supernumerary tooth germs that correlated with down regulation of Msx1 expression in the tooth mesenchyme. Taken together, our data indicate that, while reduction in mesenchymal Bmp4 expression alone could not account for the tooth bud arrest phenotype in Msx1-/- mutant mice, Bmp4 signaling synergizes with Msx1 and antagonizes Osr2 to activate mesenchymal odontogenic activity to drive tooth morphogenesis and sequential tooth formation. E13.5 mouse embryos tooth germs were microdissected by laser capture microdissection (LCM), and the mandibular molar and maxillary molar were separated. 3 pairs of control and mutant samples were pooled for the RNA extraction.
2013-01-22 | E-GEOD-39918 | biostudies-arrayexpress
Project description:Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma, NOS (PIOC), is one of the OGTs, but it is even rarer and has a worse prognosis. The characteristics of PIOC, especially in immunohistochemical features and its pathogenesis, remain unclear. We characterized a case of PIOC arising from the left mandible, in which histopathological findings showed a transition between the odontogenic keratocyst and the carcinoma. The tumorous lesion of this PIOC exhibited malignant potentials with an invasive growth of carcinoma cells into the bone tissue, an elevated Ki-67 index, and lower signal for CK13 and higher signal for CK17 compared with the non-tumor region, histopathologically and immunohistopathologically. Further immunohistochemical analyses demonstrated increased expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C) (accompanying expression of β-catenin in the nucleus) and yes-associated protein (YAP) in the tumorous lesion. On the other hand, YAP was expressed and the expression of ARL4C was hardly detected in the non-tumor region. In addition, quantitative RT-PCR analysis using RNAs and dot blot analysis using genomic DNA showed the activation of Wnt/β-catenin signaling and epigenetic alterations, such as an increase of 5mC levels and a decrease of 5hmC levels, in the tumorous lesion. A DNA microarray and gene ontology analysis demonstrated that numerous gene expression variations and signal activation, including Notch signaling, were altered in non-tumor and tumor lesions within this PIOC. Experiments with the GSK-3 inhibitor revealed that β-catenin pathway increased not only mRNA levels of ankyrin repeat domain1 (ANKRD1) but also protein levels of YAP and TAZ in oral squamous cell carcinoma cell lines. These results suggested that further activation of YAP signaling by Wnt/β-catenin signaling may be associated with the development of PIOC arising from odontogenic keratocyst in which YAP signaling is activated.
2024-01-26 | GSE253232 | GEO
Project description:Murine tooth germ development proceeds in continuous and sequential steps with reciprocal interactions between the odontogenic epithelium and the adjacent mesenchyme, and several growth factor signaling and their activation are required for tooth germ development. The expression of ADP-ribosylation factor (Arf)-like 4c (Arl4c) has been shown to induce cell proliferation, thereby involving in epithelial morphogenesis and tumorigenesis. However, other functions of Arl4c except for cellular growth are largely unknown. Although we recently demonstrated the involvement of the upregulated expression of Arl4c in cell proliferation of ameloblastoma, which has the same origin as odontogenic epithelium, its effect on tooth germ development remains unclear. Herein, single-cell RNA sequencing (scRNA-seq) analysis revealed that the expression of Arl4c, among 17 members of the Arf-family members, was specifically detected in odontogenic epithelial cells, such as stratum intermedium, stella reticulum and outer enamel epithelium, of postnatal day 1 (P1) mouse molar. In addition, scRNA-seq analysis showed higher expression of Arl4c in non-ameloblast and inner enamel epithelium, which include immature cells. In the mouse tooth germ rudiments culture, treatment with SecinH3 (an inhibitor of ARNO/Arf6 pathway) reduced the size, width and cusp height and the thickness of eosinophilic layer, which would involve the synthesis of dentin and enamel matrix organization. In addition, loss-of-function experiments using siRNAs and shRNA revealed that Arl4c expression was involved in cell proliferation and osteoblastic cytodifferentiation in odontogenic epithelial cells. Finally, RNA-seq analysis with gene set enrichment analyses (GSEA) and Gene Ontology (GO) analysis showed that osteoblastic differentiation-related gene set and/or GO terms were downregulated in shArl4c expressing odontogenic epithelial cells. These results suggest that the Arl4c-ARNO/Arf6 pathway axis contributes to tooth germ development through osteoblastic differentiation.
2023-07-01 | GSE235460 | GEO
Project description:Previous studies have suggested that Bmp4 is a key Msx1-dependent mesenchymal odontogenic signal for driving tooth morphogenesis through the bud-to-cap transition. Whereas the bud stage tooth developmental arrest in Msx1-/- mutant mice was accompanied by reduction in mesenchymal Bmp4 mRNA expression, we show that depleting functional Bmp4 mRNAs in the tooth mesenchyme, through neural crest-specific gene inactivation in Bmp4f/f;Wnt1Cre mice, caused mandibular molar developmental arrest at the bud stage but allowed maxillary molars and incisors to develop to mineralized teeth. We show that the Wnt inhibitors Dkk2 and Wif1 were much more abundantly expressed in the mandibular than maxillary molar mesenchyme in wildtype embryos and that Dkk2 expression was significantly unregulated in the tooth mesenchyme in Bmp4f/f;Wnt1Cre embryos. In addition, expression of Osr2, which encodes a zinc finger protein that antagonizes Msx1-mediated activation of odontogenic mesenchyme, is significantly upregulated in the molar mesenchyme in Bmp4f/f;Wnt1Cre embryos. Msx1 heterozygosity enhanced maxillary molar developmental defects whereas Osr2 heterozygosity rescued mandibular first molar morphogenesis in Bmp4f/f;Wnt1Cre mice. Moreover, in contrast to complete lack of supernumerary tooth initiation in Msx1-/-Osr2-/- mutant mice, Osr2-/-Bmp4f/f;Wnt1Cre compound mutant mice exhibit formation and subsequent arrest of supernumerary tooth germs that correlated with down regulation of Msx1 expression in the tooth mesenchyme. Taken together, our data indicate that, while reduction in mesenchymal Bmp4 expression alone could not account for the tooth bud arrest phenotype in Msx1-/- mutant mice, Bmp4 signaling synergizes with Msx1 and antagonizes Osr2 to activate mesenchymal odontogenic activity to drive tooth morphogenesis and sequential tooth formation.
2013-01-22 | GSE39918 | GEO
Project description:The odontoblasts are specialized cells responsible for dentin synthesis and nociceptive signal detection in response to external stimuli. Recent studies have shown that the mechanosensitive ion channel PIEZO1 is involved in bone formation and remodeling through the influx of calcium ions, and it is abundantly expressed in odontoblasts. However, the specific role of PIEZO1 in reactionary dentinogenesis by odontoblasts and the underlying mechanisms still remain elusive. In this study, we found intense PIEZO1 expression in the plasma membrane and cytoplasm of odontoblasts in human and mouse mandibular molars, and human odontoblast-like cells (hOBLCs). In hOBLCs, PIEZO1 positively regulated DSPP, DMP1, and COL1A1 expression through the Ca2+/PI3K-Akt/SEMA3A signaling pathway. Additionally, exogenous SEMA3A supplementation effectively reversed reduced mineralization capacity in PIEZO1-knockdown hOBLCs. In vivo, Piezo1 expression peaked at day 7 and returned to baseline at day 21 in a wild-type (WT) mice dentin injury model, with Sema3a presenting a similar expression pattern. To investigate the specific role of PIEZO1 in reactionary dentinogenesis, mice with a conditional knockout of PIEZO1 in odontoblasts were generated, and no significant differences of teeth phenotypes were observed between the control and conditional knockout (cKO) mice. Nevertheless, cKO mice exhibited reduced reactionary dentin formation, and decreased Sema3a and Dsp positive staining after dentin injury, indicating impaired dental pulp repair mediated by odontoblasts. In summary, these findings suggest that PIEZO1 enhances mineralization capacity of hOBLCs in vitro via the Ca2+/Akt/SEMA3A signaling pathway and contributes to dental pulp repair through enhancing reactionary dentinogenesis in vivo.
2025-06-30 | GSE263258 | GEO
Project description:Tooth regeneration remains an unmet clinical challenge due to the structural complexity of dental tissues and the requirement for precise epithelial–mesenchymal interactions during development. Here, we present a xeno-free, biomimetic strategy for dental organoid engineering by integrating human induced pluripotent stem cell (hiPSC)–derived oral epithelial cells (OECs) and neural crest cells (NCCs) within a biodegradable chitosan–alginate (CA) scaffold. The CA scaffold provides a mechanically compliant and highly porous 3D microenvironment that supports hiPSC maintenance, lineage-specific differentiation, and spatial organization. Recombined OECs and NCCs self-organized into dental organoids that recapitulated key features of early odontogenesis, including coordinated epithelial–mesenchymal interactions, progressive expression of odontogenic markers (DSPP and AMBN), and time-dependent mineral deposition. Transcriptomic profiling revealed activation of gene programs associated with odontogenesis, amelogenesis, and craniofacial morphogenesis. Upon orthotopic implantation into a rat maxillary molar extraction site, cell-laden scaffolds supported cell survival, early tooth-like tissue organization, and localized mineralized matrix formation in vivo. Together, these results establish a xeno-free, scaffold-based platform for dental organoid formation and early tooth regeneration, providing a translational framework for stem cell–based dental tissue engineering and regenerative therapies.
2026-02-18 | GSE319198 | GEO
Project description:Knockdown of endogenous GDF11 downregulated the odontogenic differentiation of human dental pulp stem cells (hDPSCs). We performed RNA-seq analysis on hDPSCs transfected with GDF11 small interfering RNA (siRNA) and control siRNA after 7 days of odontogenic induction, in order to investigate the underlying mechanisms of endogenous GDF11 regulating odontogenic differentiation in hDPSC.
2020-06-03 | GSE151435 | GEO