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

Cell fates are determined by specific transcriptional programs. Here we provide evidence that the transcriptional coactivator, Mediator 1 (Med1), is essential for the cell fate determination of ectodermal epithelia. Conditional deletion of Med1 in vivo converted dental epithelia into epidermal epithelia, causing defects in enamel organ development while promoting hair formation in the incisors. We identified multiple processes by which hairs are generated in Med1 deficient incisors: 1) dental epithelial stem cells lacking Med 1 fail to commit to the dental lineage, 2) Sox2-expressing stem cells extend into the differentiation zone and remain multi-potent due to reduced Notch1 signaling, and 3) epidermal fate is induced by calcium as demonstrated in dental epithelial cell cultures. These results demonstrate that Med1 is a master regulator in adult stem cells to govern epithelial cell fate.

细胞命运由特定的转录程序所决定。本研究提供证据表明，转录共激活因子中介体1（Mediator 1，Med1）对于外胚层上皮的细胞命运决定至关重要。体内条件性敲除Med1可将牙上皮转化为表皮上皮，引发牙釉质器官发育缺陷，同时促进门牙部位的毛发生成。本研究明确了Med1缺陷型门牙中毛发生成的三种机制：1）缺乏Med1的牙上皮干细胞无法向牙谱系分化；2）表达Sox2的干细胞延伸至分化区，且因Notch1信号通路活性下调而维持多能性；3）通过牙上皮细胞培养实验证实，钙信号可诱导表皮命运取向。上述结果表明，Med1是成体干细胞中调控上皮细胞命运的主调控因子。