Notch信号通过MicroRNA调控神经干细胞粘附连接及干性维持

项目名称： Notch信号通过MicroRNA调控神经干细胞粘附连接及干性维持

项目编号： No.31471044

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 郑敏化

作者单位： 中国人民解放军第四军医大学

项目金额： 86万元

中文摘要： 在哺乳类神经发育中，神经干细胞（NSCs）之间的粘附连接（AJs）是其极性排列的结构基础，而调控AJs形成及动态变化的分子机制不清。既往文献和我们的研究证明，在神经组织中特异阻断经典Notch信号后出现AJs缺陷，但其效应分子和调控环路尚不清楚。我们用Notch信号关键转录因子RBP-J条件性基因剔除小鼠培养神经球，参比正常NSC的miRNA表达谱发现：miR-582和miR-146a表达上调，前期实验和既往研究显示上述两个miRNA可靶向AJs组成分子,并前馈性调节Notch1。在此基础上，本课题拟深入研究Notch-miR-582/146a-cdh2/ctnnb1/numb-Notch1前馈环路对NSCs的AJs结构及干细胞特性的维持作用；该研究可望揭示Notch信号在体调控NSCs的新作用及新机制，还可为建立针对AJs来提升体外NSCs多潜能性及自组织能力的新的干预策略提供理论支持。

中文关键词： 神经干细胞；Notch信号途径；微小RNA；粘附连接；细胞极性

英文摘要： In the mamalian neural development, the adherens junctions (AJs) between neural stem cells (NSCs) are the structural basis of their polarized arrangement in neuroepithelium. However, the mechanisms under the formation and remodeling of AJs remained largely unkown. Previous studies and our research works revealed that the conditional blockade of Notch signaling in neural tissues resulted in defective AJs, whereas the dowstream effectors and the regulatory loop are dimness. We accumulated Notch-blockaded neurospheres from the embryonic brain of NSC-specific knockout of RBP-J, the key transcription factor under Notch receptors. Compared with the control neurospheres, miRNA array revealed upregulation of miR-582/miR-146a. Our present data and previous reports indicate that miR-582/miR-146a could target cdh2/ctnnb1 and numb, the major components and regulator of AJs, and feedforward regulate Notch1 receptor. Based on these results, this study is aimed to demonstrate the existence and function of Notch-miR-582/146a-cdh2/ctnnb1/numb-Notch1 regulatory loop in the maintenance of the AJs and stemness of NSCs. And the accomplishment of this study could reveal the novel function and mechanisms of Notch signaling on NSCs in vivo. In addition, it might brought theoretical support to the establishment of new intervention targeting AJs structure to promote the multipotency and self-organization ability of in vitro amplified NSCs.

英文关键词： Neural stem cell;Notch signaling;MicroRNA;Adherens junction;Cell polarity