Ablation of Coactivator Med1 Switches the Cell Fate of Dental Epithelia to That Generating Hair

Yoshizaki, Keigo; Hu, Lizhi; Nguyen, Thai; Saito, Kiyoshi; He, Bing; Fong, Chak; Yamada, Yoshihiko; Bikle, Daniel D.; Oda, Yuko

doi:10.1371/journal.pone.0099991

Cited by 33 publications

(49 citation statements)

References 44 publications

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“…In another study of tooth development, it was reported that deletion of Smad4 in dental epithelium resulted in ectopic activation of SHH-Gli1 signaling and ectopic Sox2+ epithelial stem cells, indicating that the BMP-SHH signaling network regulates Sox2+ epithelial stem cells in teeth40. Previously, we reported that Ca 2+ dramatically decreased Sox2+ dental epithelial stem cells in vitro , and also showed that ablation of mediator subunit 1 (MED1) resulted in switching of Sox2+ dental epithelial stem cell fate and contributed to ectopic hair formation in teeth41. These results indicated that Sox2+ cells are governed by differential signaling, which can control their cell fate.…”

Section: Discussionmentioning

confidence: 96%

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Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains

Arai

Yoshizaki

Miyazaki

et al. 2017

Sci Rep

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Tooth development is initiated by epithelial-mesenchymal interactions via basement membrane (BM) and growth factors. In the present study, we found that nephronectin (Npnt), a component of the BM, is highly expressed in the developing tooth. Npnt localizes in the BM on the buccal side of the tooth germ and shows an expression pattern opposite that of the dental epithelial stem cell marker Sox2. To identify the roles of Npnt during tooth development, we performed knockdown and overexpression experiments using ex vivo organ and dental epithelial cell cultures. Our findings showed that loss of Npnt induced ectopic Sox2-positive cells and reduced tooth germ size. Over expression of Npnt showed increased proliferation, whereas the number of Sox2-positive cells was decreased in dental epithelial cells. Npnt contains 5 EGF-like repeat domains, as well as an RGD sequence and MAM domain. We found that the EGF-like repeats are critical for Sox2 expression and cell proliferation. Furthermore, Npnt activated the EGF receptor (EGFR) via the EGF-like repeat domains and induced the PI3K-Akt signaling pathway. Our results indicate that Npnt plays a critical scaffold role in dental epithelial stem cell differentiation and proliferation, and regulates Sox2 expression during tooth development.

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Section: Discussionmentioning

confidence: 96%

“…M3H1 cells, a dental epithelial cell line, were established as we previously reported41. Briefly, dental epithelial cells were harvested from the cervical loop of mandible incisors obtained from 4-month old mice.…”

Section: Methodsmentioning

confidence: 99%

Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains

Arai

Yoshizaki

Miyazaki

et al. 2017

Sci Rep

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“…Previously, we reported that Med1 KO mice develop ectopic hair formation and hypomineralization of incisor enamel (24). Here, we re-evaluated the impact of Med1 deletion on molar enamel mineralization.…”

Section: Med1 Deficiency In Dental Epithelia Causes Defects In Enamelmentioning

confidence: 90%

“…Ten-week-old floxed Med1 mice containing the Krt14Cre transgene (KO) were compared with control (CON) littermates that had floxed Med1 alleles but no Cre. Med1 was removed from dental epithelial cells in Med1 KO teeth, as shown in our previous study (24). The Krt14Cre transgene is expressed in all dental epithelia cell lineages in the developing tooth (27).…”

Section: Med1 Deficiency In Dental Epithelia Causes Defects In Enamelmentioning

confidence: 99%

“…We generated conditional knock-out (KO) mice, in which Med1 is removed from keratin 14 (Krt14)-expressing epithelia, and used these mice to show that Med1 ablation causes defects in hair differentiation leading to alopecia in the skin (23). The same conditional Med1 KO mice, in which Med1 was also removed from Krt14-expressing dental epithelia, showed disruption in the development of incisors (24). Med1 deletion causes defects in cell fate of incisorspecific adult stem cells, resulting in ectopic hair formation in the SI while reducing mineralization of the incisor enamel.…”

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confidence: 99%

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Mediator 1 contributes to enamel mineralization as a coactivator for Notch1 signaling and stimulates transcription of the alkaline phosphatase gene

Yoshizaki

Nguyen

et al. 2017

Journal of Biological Chemistry

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Tooth enamel is mineralized through the differentiation of multiple dental epithelia including ameloblasts and the stratum intermedium (SI), and this differentiation is controlled by several signaling pathways. Previously, we demonstrated that the transcriptional coactivator Mediator 1 (MED1) plays a critical role in enamel formation. For instance, conditional ablation of in dental epithelia causes functional changes in incisor-specific dental epithelial stem cells, resulting in mineralization defects in the adult incisors. However, the molecular mechanism by which deficiency causes these abnormalities is not clear. Here, we demonstrated that ablation causes early SI differentiation defects resulting in enamel hypoplasia of the-deficient molars. deletion prevented Notch1-mediated differentiation of the SI cells resulting in decreased alkaline phosphatase (ALPL), which is essential for mineralization. However, it does not affect the ability of ameloblasts to produce enamel matrix proteins. Using the dental epithelial SF2 cell line, we demonstrated that MED1 directly activates transcription of the gene through the stimulation of Notch1 signaling by forming a complex with cleaved Notch1-RBP-Jk on the promoter. These results suggest that MED1 may be essential for enamel matrix mineralization by serving as a coactivator for Notch1 signaling regulating transcription of the gene.

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Molecular Mechanisms Regulating Tooth Number

Kawasaki

Blackburn

et al. 2016

Interface Oral Health Science 2016

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Tooth number, shape, and position are consistent in mammals and are subject to strict genetic control. Multiple signaling pathways including Shh, Tgf, Bmp, Wnt, Fgf, Notch, and NF-kB are known to play critical roles in regulating tooth development. Recent studies show that these signaling pathways interact with each other through positive and negative feedback loops to regulate tooth number, shape, and spatial pattern. Teeth develop via a dynamic and complex reciprocal interaction between dental epithelium and cranial neural crest-derived mesenchyme. These interactions contain a series of inductive and permissive processes that lead to the determination, differentiation, and organization of odontogenic cells, which are controlled by these signaling pathways. It is believed that dozens of different molecules together form complex molecular networks that regulate tooth development. Studies of human congenital disease and transgenic mice suggest that disturbance of the molecular network results in abnormal tooth formation. Since molecular mechanisms involved in tooth development should be reproduced in tooth regeneration, knowledge of tooth development from both human and mouse studies is crucial for exploring tooth regenerative therapies. In this paper, we present an overview of the current literature covering the molecular mechanisms of tooth development, especially those regulating tooth number.

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Ablation of Coactivator Med1 Switches the Cell Fate of Dental Epithelia to That Generating Hair

Cited by 33 publications

References 44 publications

Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains

Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains

Mediator 1 contributes to enamel mineralization as a coactivator for Notch1 signaling and stimulates transcription of the alkaline phosphatase gene

Molecular Mechanisms Regulating Tooth Number

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