Store-operated Ca2+ entry controls ameloblast cell function and enamel development
Store-operated Ca2+ entry controls ameloblast cell function and enamel development
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DOI：
10.1172/jci.insight.91166
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发表时间：
2017-03-01
期刊：
影响因子：
8
通讯作者：
Lacruz, Rodrigo S.
中科院分区：
文献类型：
--
作者：
Eckstein, Miriam;Vaeth, Martin;Lacruz, Rodrigo S.
基质相互作用分子1（STIM 1）的功能缺失突变损害了Ca 2+释放激活的Ca 2+（CRAC）通道和钙库操纵的Ca 2+进入（SOCE）的激活，导致称为CRAC通道病的疾病综合征，其特征是严重的牙釉质缺陷。由于缺乏动物模型，这些牙釉质缺陷的原因仍不清楚。我们产生了Stim 1/2（K14 cre）小鼠，以删除釉细胞中的STIM 1及其同源物STIM 2。这些小鼠在釉细胞中显示出受损的SOCE。Stim 1/2（K14 cre）小鼠牙釉质矿化不足，钙含量降低，机械薄弱，薄。SOCE缺陷的成釉细胞的形态发生改变，表现出典型的皱褶边界的损失，导致错误定位的线粒体。SOCE缺陷成釉细胞的全球基因表达分析揭示了几种途径的强烈失调。在Stim 1/2缺陷细胞中，与未折叠蛋白反应相关的ER应激基因增加，而谷胱甘肽系统组分的表达减少。与氧化应激增加一致，我们发现Stim 1/2（K14 cre）小鼠成釉细胞中ROS产生增加，线粒体功能降低，线粒体形态异常。总的来说，这些数据表明，釉细胞中的SOCE的损失对基因表达、细胞功能和牙釉质的矿化具有实质性的不利影响。
Loss-of-function mutations in stromal interaction molecule 1 (STIM1) impair the activation of Ca2+ release-activated Ca2+ (CRAC) channels and store-operated Ca2+ entry (SOCE), resulting in a disease syndrome called CRAC channelopathy that is characterized by severe dental enamel defects. The cause of these enamel defects has remained unclear given a lack of animal models. We generated Stim1/2(K14cre) mice to delete STIM1 and its homolog STIM2 in enamel cells. These mice showed impaired SOCE in enamel cells. Enamel in Stim1/2(K14cre) mice was hypomineralized with decreased Ca content, mechanically weak, and thinner. The morphology of SOCE-deficient ameloblasts was altered, showing loss of the typical ruffled border, resulting in mislocalized mitochondria. Global gene expression analysis of SOCE-deficient ameloblasts revealed strong dysregulation of several pathways. ER stress genes associated with the unfolded protein response were increased in Stim1/2-deficient cells, whereas the expression of components of the glutathione system were decreased. Consistent with increased oxidative stress, we found increased ROS production, decreased mitochondrial function, and abnormal mitochondrial morphology in ameloblasts of Stim1/2(K14cre) mice. Collectively, these data show that loss of SOCE in enamel cells has substantial detrimental effects on gene expression, cell function, and the mineralization of dental enamel.