Sexual identity and germ cell differentiation in the Drosophila ovary

果蝇卵巢的性别认同和生殖细胞分化

• 批准号: 8503678
• 负责人: HELEN Karen SALZ
• 金额: $ 30.12万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-06 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503678
• 关键词: 3' Untranslated Regions; Address; Adopted; Adult; Animal Model; Animal Organ; Attention; Behavior; Binding; Biochemical; Biological Assay; Biological Models; Biology; Candidate Disease Gene; Cell Differentiation process; Cell Maintenance; Cells; Data; Development; Drosophila genus; Environment; Failure; Female; Firefly Luciferases; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Techniques; Germ Cells; Germ cell tumor; Goals; Gonadal structure; Housing; Human; Insecta; Knowledge; Lead; Ligands; Maintenance; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular Genetics; Ovarian; Ovary; Pathway interactions; Process; Proliferating; Protein Biochemistry; Proteins; RNA; RNA Interference; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Renilla; Reporter; Signal Pathway; Signal Transduction; Somatic Cell; Source; Specificity; Stable Populations; Stem Cell Factor; Stem cells; System; Testing; Testis; Time; Tissues; Translational Regulation; Translational Repression; Translations; Work; cell behavior; cell type; daughter cell; gain of function; genome-wide; information model; inhibitor/antagonist; innovation; insight; male; mutant; neoplastic cell; neuronal cell body; novel; prevent; public health relevance; repaired; self-renewal; senescence; sex; stem cell fate; tissue repair; tumor

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.

描述（由申请人提供）：在成人中，组织的维护和修复取决于稳定的干细胞群，这些干细胞可以产生自我更新和分化的子细胞。了解这一过程的调节方式至关重要，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则会导致增殖细胞的积累和肿瘤形成。果蝇卵巢和睾丸（自然环境中干细胞研究的两个主要模型系统）中雄性和雌性生殖干细胞（GSC）行为的比较揭示了控制自我更新/的调节机制的性二态性适应。差异化决策。然而，很少有人关注这些差异是如何实现的。 Salz 实验室的数据支持一种新模型，其中女性特异性 RNA 结合蛋白 Sex-lethal (Sxl) 共同控制生殖系的性别认同和自我更新/分化决定。没有Sxl蛋白的GSC无法成功执行自我更新至分化细胞命运转换。分化失败伴随着一组雄性特异性标记物的不适当表达、持续增殖和肿瘤形成。 Sxl 编码普遍表达的女性特异性 RNA 结合蛋白。在体细胞中，它全局调节女性特异性的各个方面 发展和行为。然而，其在种系中的作用方式仍然知之甚少。这项新提案中的研究使用将经典和分子遗传学与 RNA/蛋白质生物化学相结合的综合实验方法来解决这个问题。在目标 1 中，我们重点关注 Sxl 如何控制生殖细胞分化，首先我们的研究表明，Sxl 通过抑制保守干细胞因子纳米的翻译来促使干细胞命运的退出。在目标 2 中，我们重点关注 Sxl 如何维持性别认同，首先进行的初步研究表明，Sxl 通过 Jak/Stat 信号通路发挥作用，抑制男性特异性生殖细胞行为。本提案中的研究产生的知识将阐明整合性别认同和性别认同的内在监管机制。 自我更新/分化决定，并将提供有关为何该途径中断导致生殖细胞肿瘤的信息。来自果蝇种系等模型系统的信息将为干细胞如何控制其他实验不易处理的系统中的自我更新/分化决策提供关键见解。更一般地说，从我们的动物模型研究中获得的信息将阐明 RNA 调节因子在时间和空间上差异调节基因表达的策略。