Molecular Mechanisms Regulating Drosophila Ovarian Germline Stem Cells

成体干细胞具有惊人的自我更新能力，并产生分化的细胞，以维持 成人组织中的动态平衡。它们已被证明位于利基中，并受到利基的监管。一位少校 干细胞研究中的挑战是识别和理解外在信号和内在因素的功能 来控制干细胞的自我更新。这个项目的长期目标将是获得更多的了解 利用果蝇卵巢研究干细胞自我更新如何受内在因素和生态位信号控制 生殖系干细胞(GSCs)作为模型系统。果蝇卵巢是一个值得研究的诱人系统 由于强大的遗传学和易于识别，干细胞及其在分子和细胞水平上的生态位 干细胞。我们最近发现，来自利基的GBB/BMP5-8和DPP/BMP2-4控制GSC自我 通过抑制促进分化基因bam的表达进行更新。我们还证明了E- 钙粘附素介导的细胞黏附是将GSCs锚定到它们的壁龛所必需的，而染色质 重塑因子ISWI和翻译调节因子Pelota是控制GSC自我更新所必需的。 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 自我更新。 这项拟议研究的三个具体目标是：(1)使用分子、遗传、 确定BMP信号如何与染色质相互作用的生化和细胞生物学方法 重塑因子抑制bam的表达，从而保持自我更新；(2)结合使用 分子、遗传和细胞生物学方法通过研究来研究生态位活动是如何调节的 一个新发现的生态位基因Shk与BMP途径的遗传关系；(3)分子和 确定GSC自我更新所需的基因的基因特征。这项拟议研究的结果 将使我们更好地理解利基信号和内在因素是如何协同工作来控制 GSC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，因为来自不同生物体的干细胞具有相似的“严酷” 属性。干细胞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，也与癌症和衰老有关。因此，这项拟议的研究将 当然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。

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.