Investigation of Niche Control of Germline Stem Cell Lineage Differentiation

生殖干细胞谱系分化的生态位控制研究

• 批准号: 9906238
• 负责人: TING XIE
• 金额: $ 34.24万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-03 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906238
• 关键词: Address; Adhesions; Aging; Alzheimer' s Disease; Biological Models; Cell Adhesion; Cell Adhesion Molecules; Cell Differentiation process; Cell Lineage; Cell Therapy; Cell physiology; Cells; Cellular biology; Communication; Connexins; Degenerative Disorder; Diabetes Mellitus; Disease; Drosophila genus; Erinaceidae; Gap Junctions; Generations; Genes; Genetic; Germ Cells; Goals; Human; Instruction; Investigation; Knowledge; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Monomeric GTP-Binding Proteins; Names; Ovarian; Ovary; Parkinson Disease; Pathway interactions; Property; Proteins; Publishing; Regulation; Reproductive Biology; Research; Salsola; Signal Repression; Signal Transduction; Stem Cell Development; Study models; WNT Signaling Pathway; autocrine; cancer stem cell; fight against; germline stem cells; human disease; insight; novel; overexpression; prevent; protein function; rho GTPase-activating protein; self-renewal; stem cell differentiation; stem cell therapy; stem cells; tool

Project Summary Investigation of Niche Control of Germline Stem Cell Lineage Differentiation The long-term objective of this proposed study is to investigate how niche-mediated cellular interactions control stem cell lineage differentiation extrinsically. Stem cells have the ability to continuously self-renew and produce differentiated progeny. The mechanisms controlling stem cell lineage differentiation are critical for using stem cells in treating human diseases, such as Parkinson’s, Alzheimer’s and diabetes, as well as for fighting against cancer and aging. Germline stem cells (GSCs) in the Drosophila ovary are an effective model for studying stem cell self-renewal and lineage differentiation and for studying reproductive biology because of powerful genetic tools and exceptional cell biology. We have recently proposed that somatic escort cells (ECs) from a niche for GSC progeny differentiation in the Drosophila ovary, which is named as the differentiation niche. However, it remains largely unknown how niche-mediated cellular interactions control GSC progeny differentiation at the molecular level. We have shown that autocrine Hedgehog (Hh) signaling and Wnt signaling function in ECs to control GSC progeny differentiation by maintaining EC cellular processes and/or repressing BMP signaling. Excitingly, our preliminary results have also shown that: 1) Hh/Wnt signaling represses the expression of BMP signaling regulators dally-like protein (dlp) and magu, which overexpression elevates BMP signaling in GSC progeny; 2) Hh/Wnt signaling represses the expression of small GTPase regulators RhoGAP54D and tumbleweed (tum), which overexpression leads to the EC cellular process loss; 3) three gap junction proteins function in ECs to promote GSC progeny differentiation, and one of them is also required in ECs to maintain their long cellular processes. The goal of this project is to use the Drosophila ovary as a model to gain a better understanding of how the niche controls GSC lineage differentiation at the molecular level. Three specific aims of this proposed study are to investigate 1) if Wnt and Hh pathways maintain EC cellular processes by repressing the expression of RhoGAP54D and tum; 2) if Hh and Wnt pathways prevent BMP signaling in GSC progeny by repressing the expression of magu and dlp; 3) how gap junctions maintain EC cellular process-germ cell adhesion and control GSC progeny differentiation. Because the molecular mechanisms controlling stem cell differentiation are important for providing functional cells for cell therapy, preventing cancer stem cell expansion, and slowing down aging, the knowledge gained from this proposed study is critical for treating human degenerative diseases and for fighting against cancer and aging. Since many properties of germ cells are conserved from Drosophila to human, the findings from this study will also help gain a better understanding of human reproductive biology.

项目摘要 生殖线控制干细胞谱系分化的生态位控制的研究 这项拟议的研究的长期目标是研究小众介导的细胞相互作用如何控制 干细胞谱系外部分化。干细胞具有继续自我更新并产生的能力 分化后代。控制干细胞谱系分化的机制对于使用Stem至关重要 治疗人类疾病的细胞，例如帕金森氏症，阿尔茨海默氏症和糖尿病，以及与之抗争 癌症和衰老。果蝇卵巢中的种系干细胞（GSC）是研究的有效模型 干细胞的自我更新和谱系分化，并用于研究生殖生物学 遗传工具和特殊的细胞生物学。我们最近提出了来自A的体细胞（EC） 果蝇卵巢中GSC后代分化的利基市场，该卵巢被称为分化位。 然而，在很大程度上仍然未知小众介导的细胞相互作用如何控制GSC后代 分子水平的分化。我们已经证明了自分泌刺猬（HH）信号和wnt 通过维持EC细胞过程和/或 抑制BMP信号。令人兴奋的是，我们的初步结果也表明：1）HH/WNT信号传导 抑制BMP信号调节剂Dally-like蛋白（DLP）和MAGU的表达，这过表达 提高GSC后代中的BMP信号传导； 2）HH/WNT信号反映了小GTPase的表达 监管机Rhogap54d和Tumbleweed（TUM），过表达导致EC细胞过程丢失； 3） EC中的三个间隙连接蛋白功能促进GSC后代分化，其中之一也是 在EC中需要长时间的细胞过程。该项目的目的是使用果蝇卵巢 作为一个模型，可以更好地了解利基市场如何控制GSC谱系分化 分子水平。这项拟议的研究的三个具体目的是研究1）如果Wnt和HH途径 通过反映Rhogap54d和TUM的表达来维持EC细胞过程； 2）如果HH和Wnt 途径通过反映MAGU和DLP的表达来防止GSC后代中的BMP信号传导； 3）如何差距 连接保持EC细胞过程响应细胞粘合剂和控制GSC进度分化。因为 控制干细胞分化的分子机制对于提供功能细胞很重要 细胞疗法，防止癌症干细胞扩张并减慢衰老，从中获得的知识 拟议的研究对于治疗人类退行性疾病以及与癌症和衰老作斗争至关重要。 由于生殖细胞的许多特性都是从果蝇到人的保守的，因此这项研究的发现将 还有助于更好地了解人类繁殖生物学。

项目成果

Drosophila YBX1 homolog YPS promotes ovarian germ line stem cell development by preferentially recognizing 5-methylcytosine RNAs.

果蝇 YBX1 同源物 YPS 通过优先识别 5-甲基胞嘧啶 RNA 促进卵巢生殖系干细胞发育。

• DOI: 10.1073/pnas.1910862117
• 发表时间: 2020
• 期刊: Proc Natl Acad Sci U S A.
• 作者: Fan Zou;Renjun Tu;Bo Duan;Zhenlin Yang;Zhaohua Ping;Xiaoqing Song;Shiyuan Chen;Andrew Price;Hua Li;Allison Scott;Anoja Perera;Sisi Li;Ting Xie
• 通讯作者: Ting Xie