The Endoplasmic Reticulum Stress Transducer OASIS Is involved in the Terminal Differentiation of Goblet Cells in the Large Intestine
The Endoplasmic Reticulum Stress Transducer OASIS Is involved in the Terminal Differentiation of Goblet Cells in the Large Intestine
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DOI：
10.1074/jbc.m111.332593
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发表时间：
2012-03-09
影响因子：
4.8
通讯作者：
Imaizumi, Kazunori
中科院分区：
文献类型：
--
作者：
Asada, Rie;Saito, Atsushi;Imaizumi, Kazunori
OASIS是一种位于内质网（ER）中的碱性亮氨酸拉链跨膜转录因子，其响应于ER应激而在其跨膜区被切割。这种新型的ER应力传感器已被证明在成骨细胞和星形胶质细胞中表达，并促进这些细胞的终末成熟。此外，OASIS在大肠的杯状细胞中高度表达。在这项研究中，我们研究了OASIS在大肠杯状细胞分化中的作用。为了分析OASIS在杯状细胞中的功能，我们检测了Oasis（-/-）小鼠大肠的形态学变化和杯状细胞分化标志物的表达。通过破坏Oasis基因，大肠中杯状细胞的数量和粘液的产生减少。Oasis（-/-）杯状细胞形态异常，粘液囊泡和内质网粗糙。在Oasis（-/-）小鼠中，成熟杯状细胞标志物的表达水平较低，相反，早期杯状细胞标志物的表达水平较高，表明Oasis（-/-）小鼠中从早期到成熟杯状细胞的分化受损。为了确定OASIS与参与杯状细胞分化的其他因素的关联，使用细胞培养模型进行体外实验。我们发现OASIS在分化的杯状细胞中诱导的轻度ER应激反应中被激活。Oasis转录本的敲低扰乱杯状细胞终末分化。总之，我们的数据表明，OASIS在促进大肠早期杯状细胞分化为成熟杯状细胞方面起着至关重要的作用。
OASIS is a basic leucine zipper transmembrane transcription factor localized in the endoplasmic reticulum (ER) that is cleaved in its transmembrane region in response to ER stress. This novel ER stress transducer has been demonstrated to express in osteoblasts and astrocytes and promote terminal maturation of these cells. Additionally, OASIS is highly expressed in goblet cells of the large intestine. In this study, we investigated the roles of OASIS in goblet cell differentiation in the large intestine. To analyze the functions of OASIS in goblet cells, we examined morphological changes and the expression of goblet cell differentiation markers in the large intestine of Oasis(-/-) mice. By disrupting the Oasis gene, the number of goblet cells and production of mucus were decreased in the large intestine. Oasis(-/-) goblet cells showed abnormal morphology of mucous vesicles and rough ER. The expression levels of mature goblet cell markers were lower, and conversely those of early goblet cell markers were higher in Oasis(-/-) mice, indicating that differentiation from early to mature goblet cells is impaired in Oasis(-/-) mice. To determine the association of OASIS with other factors involved in goblet cell differentiation, in vitro experiments using a cell culture model were performed. We found that OASIS was activated in response to mild ER stress that is induced in differentiating goblet cells. Knockdown of the Oasis transcript perturbed goblet cell terminal differentiation. Together, our data indicate that OASIS plays crucial roles in promoting the differentiation of early goblet cells to mature goblet cells in the large intestine.