The identification of novel components of the Drosophila JAK/STAT pathway

JAK/STAT信号转导通路在整个进化过程中是保守的，并与一些白血病和包括造血在内的发育事件有关。因此，在体外和组织培养系统中进行了大量的工作，以表征该途径的成分和功能。然而，目前还没有基于基因的方法来确定途径成分。因此，我建议进行系统的遗传筛选，以分离与果蝇中保守的JAK/STAT通路相互作用的基因。我已经开发了一种果蝇种群，它在眼睛中过度表达果蝇JAK/STAT通路配体并导致细胞过度增殖。这种增殖产生大量的过度生长和成人眼睛的扩大，这在双目显微镜下很容易看到，并且依赖于下游通路成分的信号。初步结果表明，筛选是可行的，并确定了包含相互作用基因的基因组区域。一个小规模的预筛选已经确定了一些似乎参与JAK/STAT信号传导的基因。其中两个含有p元素插入，代表已知的肿瘤抑制因子和锌指蛋白的同源物。将对筛选确定的基因的功能进行后续调查，并分析它们在JAK/STAT信号传导和发育中的作用。从长远来看，希望能够识别JAK/STAT信号通路的新成分，并了解调节其活性的机制。

The JAK/STAT signal transduction pathway has been conserved throughout evolution and has been implicated in some leukemias and developmental events including haematopoiesis. As a result considerable work has been undertaken in vitro and in tissue culture systems to characterise the components and functions of the pathway. However no genetically based approach to identifying pathway components has yet been undertaken. I therefore propose to undertake a systematic genetic screen to isolate genes which interact with the JAK/STAT pathway conserved in Drosophila. I have developed a Drosophila stock that over-expresses the fly JAK/STAT pathway ligand in the eye and results in cellular over-proliferation. This proliferation produces a massive overgrowth and enlargement of the adult eye that is both easily visible in a binocular microscope and dependent on signalling by the downstream pathway components. Initial results indicate that the screen is feasible and have defined genomic regions that contain interacting genes. A small scale pre-screen has identified a number of genes that appear to be involved in JAK/STAT signalling. Two of these contain P-element insertions and represent a homologue of a known tumour suppresser and a zinc finger protein. Follow up investigations into the function of genes identified by the screen will be undertaken and their role in JAK/STAT signalling and development will be analysed. In the long term, it is hoped to be able to identify novel components of the JAK/STAT signalling pathway and understand the mechanisms that regulate its activity.