Sexual identity and germ cell differentiation in the Drosophila ovary

在成人中，组织的维持和修复依赖于稳定的干细胞群体 可以同时产生自我更新和分化的子代细胞。一种理解 这一过程是如何被监管的，这是至关重要的，因为 分化会导致干细胞枯竭和组织衰老，而分化失败 进入分化途径会导致增殖细胞的积累和 肿瘤的形成。雄性和雌性生殖系干细胞(GSC)行为的比较 果蝇卵巢和睾丸--研究干细胞的两个主要模型系统 细胞在其自然环境中，揭示了 管理自我更新/差异化决策的监管机制。一点儿 然而，人们一直关注这些差异是如何实现的。不断涌现的数据 Salz实验室支持一种新的模型，在该模型中女性特定的RNA结合 蛋白性致死蛋白(SXL)共同控制性认同和自我- 种系的更新/分化决策。没有SXL蛋白的GSCs无法 成功执行自我更新以分化细胞命运的切换。未能做到 分化伴随着一组男性特有的不适当的表达 标记物，肿瘤的持续增殖和形成。SXL编码无处不在的 表达女性特异的RNA结合蛋白。在体细胞中，它全局调节所有 女性特有的发展和行为方面。它在生殖系中的作用方式， 然而，人们对此仍知之甚少。这项新建议中的研究解决了这个问题。 使用经典遗传学和分子遗传学相结合的综合实验方法 核糖核酸/蛋白质生物化学。具体地说，我们关注的是SXL如何维持性行为 身份，从初步研究开始，表明SXL通过JAK/STAT起作用 抑制男性特定生殖细胞行为的信号通路。所产生的知识 通过本提案中的研究，将阐明 整合性别认同和自我更新/差异化决策，并将提供 关于为什么这一途径的中断会导致生殖细胞肿瘤的信息。信息 从模型系统，如果蝇种系，将提供关键的见解如何 干细胞控制自我更新/分化的决定在其他方面，实验较少。 易于管理的系统。更广泛地说，从我们的动物模型研究中获得的信息 将说明RNA调节器用于差异调控基因的策略 在时间和空间上的表达。

In adults, tissue maintenance and repair depends on a stable population of stem cells that can give rise to both self-renewing and differentiating daughter cells. An understanding of how this process is regulated is of fundamental importance because an excess of differentiation can lead to stem cell depletion and tissue senescence, while a failure to enter the differentiation pathway can lead to an accumulation of proliferating cells and tumor formation. A comparison of male and female germline stem cell (GSC) behavior in Drosophila ovaries and testis, two of the premier model systems for the study of stem cells in their natural environment, reveals sexually dimorphic adaptations of the regulatory mechanisms governing the self-renewal/differentiation decision. Little attention, however, has been paid to how these differences are achieved. Data emerging from the Salz lab supports a novel model in which the female specific RNA binding protein Sex-lethal (Sxl) jointly controls sexual identity and the self- renewal/differentiation decision in the germline. GSCs without Sxl protein fail to successfully execute the self-renewal to differentiation cell fate switch. The failure to differentiate is accompanied by the inappropriate expression of a set of male specific markers, continued proliferation and formation of a tumor. Sxl encodes a ubiquitously expressed female-specific RNA binding protein. In somatic cells it globally regulates all aspects of female-specific development and behavior. Its mode of action in the germline, however, remains poorly understood. The studies in this new proposal address this issue using an integrated experimental approach that combines classical and molecular genetics with RNA/protein biochemistry. Specifically, we focus on how Sxl maintains sexual identity, beginning with preliminary studies showing that Sxl acts through the Jak/Stat signaling pathway to repress male-specific germ cell behavior. The knowledge generated by the studies in this proposal will illuminate the intrinsic regulatory mechanisms that integrates sexual identity and the self-renewal/differentiation decision, and will provide information about why disruptions in this pathway lead to germ cell tumors. Information from model systems such as the Drosophila germline will provide key insights into how stem cells control the self-renewal/differentiation decision in other, less experimentally tractable systems. More generally, the information gained from our animal model studies will illuminate strategies used by RNA regulators to differentially regulate gene expression in time and space.