CONTROL OF CELL DIFFERENTIATION BY NOTCH SIGNALING

Notch信号通路在许多动物（包括哺乳动物、爪蟾、秀丽隐杆线虫和果蝇）介导细胞间相互作用中起关键作用。在许多发育中的组织中，这些notch介导的细胞信号传导过程对于细胞命运的正确分配至关重要。人类Notch活性失调与癌症有关，包括急性淋巴细胞白血病、急性髓母细胞白血病和卵巢癌。Notch信号的一个被充分研究的例子是在果蝇机械感觉刚毛的四个细胞之间调节细胞命运规范。广泛表达的转录因子Suppressor of Hairless [Su(H)]是这些细胞中Notch信号的主要换能器。我们发现，Su(H) mRNA和蛋白水平仅在果蝇的一种细胞类型中大幅增加，即机械感觉刚毛的窝细胞，这种上调似乎是由于一种高度细胞特异性的增强子，这种增强子仅在窝细胞中活跃。我们希望将窝细胞的分化作为一个模型系统来研究高度保守的、多用途的信号通路如何指导物种特异性、组织特异性和细胞特异性的分化程序。我们希望以多种方式使用Su(H)插槽增强子，使用遗传和生化方法，使我们能够识别细胞信号传导和细胞分化之间的联系。

The Notch signaling pathway plays an key role in mediating cell-cell interactions in many animals, including mammals, Xenopus, C. elegans, and Drosophila. In many developing tissues, these Notch-mediated cell signaling processes are essential for proper assignment of cell fates. Dysfunctional Notch activity in humans is associated with cancers, including acute lymphoblastic leukemia, acute myeloblastic leukemia and ovarian carcinoma. One well-studied instance of Notch signaling is in regulating cell fate specification among the four cells of the mechanosensory bristle in Drosophila. The broadly expressed transcription factor Suppressor of Hairless [Su(H)] is the primary transducer of the Notch signal in these cells. We have found that Su(H) mRNA and protein levels are greatly increased in only one cell type in Drosophila, the socket cell of the mechanosensory bristle, and that this up-regulation seems to be due to a highly cell-specific enhancer which is active only in the socket cell. We wish to study the differentiation of the socket cell as a model system for investigating the way in which highly conserved, multipurpose signaling pathways can direct species-specific, tissue-specific, and cell-specific differentiative programs. We hope to use the Su(H) socket enhancer in several ways, using both genetic and biochemical approaches, to allow us to identify the links between cell signaling and cell differentiation.