SNX17通过配体转运调节Notch信号通路及细胞命运决定的机制研究

项目名称： SNX17通过配体转运调节Notch信号通路及细胞命运决定的机制研究

项目编号： No.31271502

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 舒晓东

作者单位： 中国科学院广州生物医药与健康研究院

项目金额： 80万元

中文摘要： Notch信号通路在多种谱系细胞的命运决定过程中起着重要的作用，该通路的激活通常需要Notch配体经过修饰/内吞/循环等'活化'过程，但目前对于该过程的具体机制还很有争议。我们在前期工作中发现SNX17是个新型的Notch通路调控因子。SNX17属于一类位于内含体中、能调控囊泡运输的蛋白。SNX17在表达Notch配体的细胞中起作用，它不影响配体的内吞但能调节细胞膜上配体的蛋白水平。在斑马鱼模型中，SNX17通过Notch通路在胰腺及神经细胞的命运决定中起重要作用。我们拟进一步利用细胞和斑马鱼模型，结合生化、细胞、遗传学及发育生物学的各种技术，阐明SNX17通过对配体修饰/转运/循环/降解等步骤的可能调节作用激活Notch通路的机制，分析SNX17/Notch通路在胰腺各谱系细胞命运决定中的作用，并探索该信号通路在体外ES/iPS细胞向胰腺beta-细胞定向分化中可能的应用。

中文关键词： SNX17；Notch；泛素化；纤毛发生；斑马鱼

英文摘要： Notch is one of the most important signaling pathways involved in cell fate determination in multiple tissues. Notch ligands are activated through processes including ubiquitylation, endocytosis, recycling, etc., however, the exact molecular mechanism of ligand activation remains controversial. We recently identified SNX17 as a novel regulator of Notch pathway. Biochemically, SNX17 is an endosome protein involved in vesicular trafficking. We found that SNX17 is specifically required in the ligand-expressing cells for Notch activation. SNX17 is not involved in the endocytosis of ligand; however, it regulates the ligand protein level on the plasma membrane. We further demonstrated that SNX17-mediated Notch activation plays critical roles in pancreatic and neuronal cell fate determination during zebrafish embryogenesis. We propose to investigate the molecular mechanism of SNX17-induced Notch activation, including its potential role in processes such as ligand ubiqitylation, endocytosis, intracellular trafficking, recycling, degradation, etc.. We will characterize the role of SNX17/Notch pathway in pancreatic cell fate determination in the zebrafish model; elucidate the upstream and downstream signaling events involved. We will then use this knowledge to study the targeted differentiation of ESCs/iPSCs to the insuli

英文关键词： SNX17；Notch；Ubiquitination；Ciliogenesis；Zebrafish