REGULATION OF GERMLINE STEM CELL DIVISION IN DROSOPHILA

我们的长期目标是了解干细胞的自我更新不对称分裂是如何实现的，这是一个对理解组织发育/修复、肿瘤发生、免疫缺陷和不孕不育至关重要的问题。我们的重点一直是在果蝇生殖系干细胞中解决这个问题，首先通过鉴定这些细胞并揭示它们分裂的自我更新的不对称性，然后是对潜在机制的遗传剖析。这导致了对生殖系干细胞更新至关重要的Piwi、Yb、Pumilio(Pum)和Art(ARET)基因的发现。我们的工作假设是生殖系干细胞的自我更新能力是由表达Yb/piwi/HH的顶端体细胞发出的信号诱导的。体细胞诱导是通过控制干细胞和其分化的子代成囊细胞之间关键蛋白质的不对称分布来实现的，这决定了它们特定的命运。这些关键蛋白包括调节差异翻译的PUM，促进成囊细胞分化的BAM，以及作为干细胞分裂的细胞自主启动子在生殖系中表达的PIWI。我们的具体目标是通过系统地测试和扩展这一假说来探索干细胞的机制。有了所有的工具和在以下大多数分析中的经验，我们建议：1.分析PIWI作为核因子在生殖系干细胞分裂中的生化作用。2.研究Yb在生殖系干细胞分裂信号中的发育作用。3.分析YB在细胞信号转导中的生化作用。4.确定参与产生躯体信号的基因之间的调控关系。5.通过基因抑制筛选发现与piwi相互作用的新基因。

Our long term goal is to learn how the self-renewing asymmetric division of stem cells is achieved, a question crucial to the understanding of tissue development/repair, oncogenesis, immunodeficiency, and sterility. Our focus has been to address this question in Drosophila germline stem cells, initially by identifying these cells and revealing the self-renewing asymmetry of their division, followed by genetic dissection of the underlying mechanism. This leads to the finding of piwi, Yb, pumilio (pum), and arrest (aret) genes essential for germline stem cell renewal. Our working hypothesis is that the self- renewing ability of germ-line stem cells is induced by signaling from Yb/piwi/hh-expressing apical somatic cells. The somatic induction is achieved by controlling the asymmetric distribution of key proteins between the stem cell and its differentiated daughter, the cystoblast, which renders their specific fates. Such key proteins include PUM which regulates differential translation, BAM which promotes cystoblast differentiation and PIWI which is also expressed in the germline as a cell-autonomous promoter of stem cell division. Our specific aims are to explore the stem cell mechanism by systematically testing and expanding this hypothesis. With all the tools in place and experience in most of the following analyses, we propose to: 1. Analyze the biochemical role of PIWI as a nuclear factor in germline stem cell division. 2. Examine the developmental role of Yb in signaling germline stem cell division. 3. Analyze the biochemical role of YB in signaling cells. 4. Define regulatory relationship between genes involved in producing somatic signals. 5. Identify new genes interacting with piwi by genetic suppressor screens.