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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

基本信息

批准号：
9088475
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-06 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9088475
关键词：
Address Adopted Adult Animal Model Animal Organ Attention Behavior Biological Models Biology Candidate Disease Gene Cell Differentiation process Data Development Drosophila genus Environment Failure Female Gene Expression Gene Targeting Genes Genetic Techniques Genetic study Germ Cells Germ cell tumor Goals Gonadal structure Housing Human Insecta Knowledge Lead Ligands Maintenance Malignant - descriptor Malignant Neoplasms Modeling Molecular Genetics Ovary Pathway interactions Process Proliferating Protein Biochemistry Proteins RNA RNA Interference RNA-Binding Proteins Signal Pathway Signal Transduction Somatic Cell Source Stable Populations Stem cells System Testis Time Tissues Work cell behavior daughter cell gain of function genome-wide germline stem cells information model innovation insight male mutant neoplastic cell neuronal cell body novel prevent repaired self-renewal senescence sex stem cell fate tissue repair tumor

项目摘要

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.

在成年人中，组织的维持和修复依赖于稳定的干细胞群体，可以产生自我更新和分化的子细胞。的理解这一过程是如何调节是至关重要的，因为过量的分化可能导致干细胞耗竭和组织衰老，而不能分化则可能导致干细胞衰竭和组织衰老。进入分化途径可导致增殖细胞的积累，肿瘤形成比较男性和女性生殖系干细胞（GSC）的行为，果蝇卵巢和睾丸--干细胞研究的两个主要模型系统细胞在自然环境中，揭示了性的二态适应，自我更新/分化决定的调节机制。小然而，人们注意到如何实现这些差异。出现的数据 Salz实验室的研究支持了一种新的模型，在这种模型中，蛋白质性致死（Sxl）共同控制性身份和自我，生殖系中的更新/分化决定。没有Sxl蛋白的GSC不能成功地执行了自我更新到分化的细胞命运转换。未能分化伴随着一套男性特有的不恰当的表达，标志物，持续增殖和肿瘤形成。Sxl编码一种普遍存在的表达雌性特异性RNA结合蛋白。在体细胞中，它全面调节所有女性特有的发展和行为。它在生殖细胞中的作用方式，然而，人们对它的了解仍然很少。这项新提案中的研究涉及这一问题使用结合经典和分子遗传学的综合实验方法， RNA/蛋白质生物化学具体来说，我们关注SXL如何保持性身份，从初步研究开始，表明Sxl通过Jak/Stat 信号通路来抑制雄性特异性生殖细胞行为。产生的知识通过本提案中的研究，将阐明内在的调节机制，整合性别认同和自我更新/分化的决定，并将提供关于为什么这一途径的中断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，较少实验易处理的系统更普遍地说，从我们的动物模型研究中获得的信息将阐明RNA调节器用于差异调节基因的策略，时间和空间的表达。