FRINGE-DEPENDENT CELL-SIGNALING

这个项目旨在理解两者的作用机制 以及边缘基因的发育功能。刘易斯是第一个 在果蝇中根据其控制生长和生长的作用而被鉴定 机翼上的花纹。多个条纹相关基因现在已经被 在包括人类在内的几个不同的动物物种中被鉴定。这些 边缘基因似乎定义了一个新的细胞信号分子家族 具有独特的、特定于边界的信号模式。哺乳动物的边缘 基因在广泛的组织中表达；它们在神经中的表达 而造血组织尤其耐人寻味，因为它 与Notch信号成员的表达和功能重叠 路径。在果蝇中，流苏影响细胞命运并诱导生长 至少在一定程度上是通过调节这一途径。异常Notch信号 与小鼠乳腺癌和人类急性白血病有关联 淋巴母细胞性T细胞白血病。条纹与凹槽的相交 信号表明，条纹可能与这些癌症有关。 已知的条纹功能大部分来自对其功能的研究 在单个组织中活动，果蝇的翅膀。此外，虽然 对条纹信号的最终分子反应已经被确定， 边缘组织的直接目标仍不得而知。这项提案将解决 我们在实验中对条纹活动的理解上的这些差距 黑腹果蝇提供的顺从系统。 以确认边缘蛋白是分泌的，并深入了解其 独特的边界特定作用、细胞和亚细胞分布 边缘蛋白的含量将通过免疫定位在 果蝇的翅膀。以确定不同的发展角色 边缘是否可以发挥作用，其活动是否总是特定于边界，以及 它的信号是否总是与Notch活动、边缘活动 将在其他果蝇组织中进行研究。在这些研究中， 条纹会改变条纹活动的时间和空间模式 在转基因动物中的突变和错误表达。识别其他 条纹信号所需的基因，如假定的条纹 受体，将进行基因筛查，以寻找起到 减少条纹信号的主要增强剂。在这种情况下发现的基因 Screen将通过一系列测试来确认他们在 条纹信号，然后进行分子分析。最后，两国关系 Notch信号通路的边缘活性将在 使用已建立的细胞培养方法进行详细分析。

This project is directed toward understanding both the mechanism of action and developmental functions of the fringe gene. Fringe was first identified in Drosophila based on its role in controlling growth and patterning in the wing. Multiple fringe-related genes have now been identified in several different animal species, including humans. These fringe genes appear to define a new family of cell-signaling molecules with a unique, boundary-specific, mode of signaling. Mammalian fringe genes are expressed in a wide range of tissues; their expression in neural and hematopoietic tissues is particularly intriguing because of its overlap with the expression and function of members of the Notch signaling pathway. In Drosophila, fringe effects cell fates and induces growth at least in part through regulation of this pathway. Aberrant Notch signaling has been implicated in both murine breast cancer and human acute lymphoblastic T-cell Leukemia. The intersection of fringe with Notch signaling suggests that fringe could be relevant to these cancers. Most of what is known of how fringe functions comes from studies of its activity in a single tissue, the Drosophila wing. In addition, although ultimate molecular responses to fringe signaling have been identified, the immediate targets of fringe remain unknown. This proposal will address these gaps in our understanding of fringe activity in the experimentally amenable system provided by Drosophila melanogaster. To confirm that fringe protein is secreted and to gain insights into its unique boundary-specific action, the cellular and subcellular distribution of fringe protein will be determined by immunolocalization in the Drosophila wing. To determine the different developmental roles that fringe can play, whether its activity is always boundary specific, and whether its signaling is always tied to Notch activity, fringe activity will be investigated in other Drosophila tissue. For these studies the temporal and spatial patterns of fringe activity will be altered by fringe mutation and by mis-expression in transgenic animals. To identify other genes required for fringe signaling, such as the postulated fringe receptor, a genetic screen will be undertaken for mutations that act as dominant enhancers of reduced fringe signaling. Genes identified in this screen will be taken through a battery of tests to confirm their role in fringe signaling, and then analyzed molecularly. Finally, the relationship of fringe activity to the Notch signaling pathway will be investigated in detail using an established cell culture assay.