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 生殖系干细胞分化的生态位调控研究 这项拟议研究的长期目标是调查生态位介导的细胞相互作用是如何控制的 干细胞系的外源性分化。干细胞具有持续自我更新和产生 分化的后代。干细胞谱系分化的控制机制是干细胞利用的关键 细胞用于治疗人类疾病，如帕金森氏症、阿尔茨海默氏症和糖尿病，以及用于对抗 癌症和衰老。果蝇卵巢生殖系干细胞(GSCs)是一种有效的研究模型 干细胞的自我更新和谱系分化以及用于生殖生物学研究的强大 基因工具和特殊的细胞生物学。我们最近提出了一种新的研究方法，即从 果蝇卵巢中GSC后代分化的生态位，称为分化生态位。 然而，很大程度上仍不清楚小生境介导的细胞相互作用如何控制GSC后代。 在分子水平上的分化。我们已经证明了自分泌Hedgehog(HH)信号和WNT 内皮细胞中的信号功能，通过维持EC细胞过程和/或控制GSC后代的分化 抑制BMP信号。令人兴奋的是，我们的初步结果还表明：1)HH/WNT信号 抑制BMP信号调节因子Dally-like Protein(DLP)和MAGU的过度表达 上调GSC子代BMP信号；2)HH/WNT信号抑制小GTP酶的表达 调节剂RhoGAP54D和Tm，过表达导致EC细胞加工丢失；3) 有三种缝隙连接蛋白在内皮细胞中起促进GSC后代分化的作用，其中一种也是 是内皮细胞维持其长细胞过程所必需的。这个项目的目标是利用果蝇的卵巢 作为一个模型，以更好地了解利基如何控制GSC在 分子水平。这项拟议研究的三个具体目标是研究1)Wnt和HH通路 通过抑制RhoGAP54D和TOM的表达来维持EC的细胞进程；2)如果HH和WNT 途径通过抑制MAGU和DLP的表达来阻止GSC后代的BMP信号传导；3)How GAP 连接维持EC细胞过程-生殖细胞的黏附，并控制GSC后代的分化。因为 控制干细胞分化的分子机制对于为 细胞治疗，防止癌症干细胞扩张，减缓衰老，从这一点上获得的知识 拟议中的研究对于治疗人类退行性疾病以及抗击癌症和衰老至关重要。 由于生殖细胞的许多特性从果蝇到人类都是保守的，这项研究的发现将 也有助于更好地了解人类生殖生物学。

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