Sexual identity and germ cell differentiation in the Drosophila ovary

描述（由申请人提供）：在成人中，组织的维持和修复依赖于稳定的干细胞群体，这些干细胞可以产生自我更新和分化的子细胞。了解这一过程是如何被调节的是至关重要的，因为过度分化会导致干细胞耗竭和组织衰老，而未能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）在果蝇卵巢和睾丸（干细胞在自然环境中研究的两个主要模型系统）中的行为比较揭示了自我更新/分化决策调节机制的两性二态适应。然而，很少有人注意到这些差异是如何实现的。来自Salz实验室的数据支持了一个新的模型，在这个模型中，雌性特异性RNA结合蛋白性致死性（Sex-lethal, Sxl）共同控制着生殖细胞的性别认同和自我更新/分化决定。缺乏Sxl蛋白的GSCs无法成功执行自我更新到分化细胞的命运开关。分化的失败伴随着一组男性特异性标记的不适当表达，持续的增殖和肿瘤的形成。Sxl编码一种普遍表达的女性特异性RNA结合蛋白。在体细胞中，它全局调节女性特有的所有方面

DESCRIPTION (provided by applicant): 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. In Aim 1 we focus on how Sxl controls germ cell differentiation, beginning with our studies showing that Sxl prompts the exit from the stem cell fate by repressing translation of the conserved stem cell factor nanos. In Aim 2 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 integrate 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.