Molecular Mechanisms Regulating Drosophila Ovarian Germline Stem Cells

描述(申请人提供)：成人干细胞具有惊人的自我更新能力，并产生分化的细胞，维持成人组织的动态平衡。它们已被证明位于利基中，并受到利基的监管。干细胞研究中的一个主要挑战是识别和了解控制干细胞自我更新的外在信号和内在因素的功能。该项目的长期目标将是以果蝇卵巢生殖系干细胞(GSCs)为模型系统，更好地了解干细胞自我更新是如何由内在因素和利基信号控制的。由于强大的遗传学和易于识别的干细胞，果蝇卵巢是在分子和细胞水平上研究干细胞及其生态位的一个有吸引力的系统。我们最近发现，来自生态位的GBB/BMP5-8和DPP/BMP2-4通过抑制分化促进基因bam的表达来控制GSC的自我更新。我们还表明，E-钙粘素介导的细胞黏附是将GSC锚定到它们的壁龛所必需的，控制GSC自我更新需要染色质重塑因子ISWI和翻译调节因子Pelota。然而，在很大程度上仍然不清楚利基信号如何与内在因素合作来控制GSC的自我更新。这项拟议研究的三个具体目标是：(1)结合分子、遗传学、生化和细胞生物学方法来确定BMP信号如何与染色质重塑因子相互作用以抑制bam的表达，从而维持自我更新；(2)结合分子、遗传学和细胞生物学方法来研究如何通过研究新发现的利基基因Shk和BMP途径之间的遗传关系来调节利基活动；(3)从分子和遗传学角度描述GSC自我更新所需的基因。这项拟议研究的结果将有助于更好地理解利基信号和内在因素如何协同工作来控制GSC的自我更新。控制果蝇卵巢GSCs的机制可能是理解成年哺乳动物干细胞的基础，因为来自不同生物的干细胞具有相似的“严厉”特性。干细胞一直被倡导用于治疗各种退行性疾病，如帕金森氏症和阿尔茨海默氏症，还被认为与癌症和衰老有关。因此，这项拟议的研究必将有助于更好地了解干细胞生物学、癌症的形成和衰老，以及在未来的再生医学中使用干细胞。

DESCRIPTION (provided by applicant): Adult stem cells have remarkable ability to self-renew and generate differentiated cells that maintain homeostasis in adult tissues. They have been shown to be located in and regulated by the niche. A major challenge in stem cell research is to identify and understand functions of extrinsic signals and intrinsic factors that control stem cell self-renewal. The long-term goal of this project will be to gain a greater understanding of how stem cell self-renewal is controlled by intrinsic factors and niche signals using Drosophila ovarian germline stem cells (GSCs) as a model system. The Drosophila ovary represents an attractive system to study stem cells and their niche at the molecular and cellular level due to powerful genetics and easily identified stem cells. We have recently shown that Gbb/BMP5-8 and Dpp/BMP2-4 from the niche control GSC self- renewal by repressing expression of a differentiation-promoting gene bam. We have also shown that E- cadherin-mediated cell adhesion is required for anchoring GSCs to their niche and that a chromatin remodeling factor ISWI and a translation regulator Pelota are required for controlling GSC self-renewal. However, it still remains largely unclear how niche signals cooperate with intrinsic factors to control GSC self-renewal. Three specific aims of this proposed study are: (1) to use a combination of molecular, genetic, biochemical and cell biological approaches to determine how BMP signaling interacts with chromatin remodeling factors to repress bam expression and thereby maintain self-renewal; (2) to use a combination of molecular, genetic and cell biological approaches to investigate how niche activity is regulated by studying genetic relationships between a newly identified niche gene shk and the BMP pathway; (3) to molecularly and genetically characterize genes that are required for GSC self-renewal. The results from this proposed study will lead to a greater understanding of how niche signals and intrinsic factors work cooperatively to control GSC self-renewal. The mechanisms controlling Drosophila ovarian GSCs are likely fundamental to understanding adult mammalian stem cells since stem cells from diverse organisms share similar "sternness" properties. Stem cells have been advocated to treat a variety of degenerative diseases such as Parkinson's and Alzheimer's diseases, and have also been connected to cancer and aging. Therefore, this proposed study will surely contribute to a better understanding of stem cell biology, cancer formation and aging as well as to using stem cells in future regenerative medicine.