Mediator 1 contributes to enamel mineralization as a coactivator for Notch1 signaling and stimulates transcription of the alkaline phosphatase gene
Mediator 1 contributes to enamel mineralization as a coactivator for Notch1 signaling and stimulates transcription of the alkaline phosphatase gene
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DOI：
10.1074/jbc.m117.780866
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发表时间：
2017-07
期刊：
影响因子：
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通讯作者：
K. Yoshizaki;Lizhi Hu;Thai D. Nguyen;Kiyoshi Sakai;M. Ishikawa;I. Takahashi;S. Fukumoto;P. DenBesten;D. Bikle;Y. Oda;Yoshihiko Yamada
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文献类型：
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作者：
K. Yoshizaki;Lizhi Hu;Thai D. Nguyen;Kiyoshi Sakai;M. Ishikawa;I. Takahashi;S. Fukumoto;P. DenBesten;D. Bikle;Y. Oda;Yoshihiko Yamada
牙釉质的矿化是通过包括成釉细胞和中间层（SI）在内的多个牙上皮细胞的分化实现的，这种分化受多种信号通路的控制。在此之前，我们证明了转录共激活因子MED1在牙釉质形成中起着关键作用。例如，有条件地消融牙上皮Med1，导致门牙特异性牙上皮干细胞功能改变，导致成人门牙矿化缺陷。然而，Med1缺陷导致这些异常的分子机制尚不清楚。在这里，我们证明Med1消融导致早期SI分化缺陷，导致Med1缺失的磨牙牙釉质发育不全。Med1缺失阻止了notch1介导的SI细胞分化，导致碱性磷酸酶（ALPL）降低，而碱性磷酸酶是矿化所必需的。然而，它不影响成釉细胞产生釉质基质蛋白的能力。利用牙上皮SF2细胞系，我们证明MED1通过在Alpl启动子上与裂解的Notch1 - rbp - jk形成复合体，通过刺激Notch1信号传导直接激活Alpl基因的转录。这些结果表明MED1可能作为Notch1信号调节Alpl基因转录的辅激活因子，对釉质基质矿化至关重要。
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 Med1 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 Med1 deficiency causes these abnormalities is not clear. Here, we demonstrated that Med1 ablation causes early SI differentiation defects resulting in enamel hypoplasia of the Med1-deficient molars. Med1 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 Alpl gene through the stimulation of Notch1 signaling by forming a complex with cleaved Notch1–RBP-Jk on the Alpl 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 Alpl gene.