Investigation of Niche Control of Germline Stem Cell Lineage Differentiation

项目摘要 生殖系干细胞谱系分化的生态位控制研究 这项研究的长期目标是研究生态位介导的细胞相互作用如何控制 干细胞谱系分化研究干细胞具有不断自我更新和产生 分化后代控制干细胞谱系分化的机制对于使用干细胞是至关重要的。 细胞在治疗人类疾病，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中的生殖干细胞是研究果蝇生殖干细胞的有效模型 干细胞自我更新和谱系分化以及研究生殖生物学， 基因工具和特殊的细胞生物学。我们最近提出，体细胞护送细胞（EC）从一个 果蝇卵巢中GSC子代分化的小生境，称为分化小生境。 然而，小生境介导的细胞相互作用如何控制GSC后代仍然是一个未知数 分子水平上的差异。我们已经表明，自分泌刺猬（Hh）信号和Wnt EC中的信号传导功能，以通过维持EC细胞过程来控制GSC后代分化，和/或 抑制BMP信号传导。令人兴奋的是，我们的初步结果还表明：1）Hh/Wnt信号转导 抑制BMP信号调节剂dally-like蛋白（dlp）和magu的表达， 2）Hh/Wnt信号通路抑制小GT3的表达 调节剂RhoGAP 54 D和风滚草（tumbleweed），其过表达导致EC细胞过程损失; 3） 三种间隙连接蛋白在EC中起作用以促进GSC后代分化，并且其中一种也是 维持其长的细胞过程所必需的。这个项目的目标是利用果蝇的卵巢 作为一个模型，以更好地了解生态位如何控制GSC谱系分化， 分子水平。本研究的三个具体目标是研究1）Wnt和Hh通路 通过抑制RhoGAP 54 D和tum的表达来维持EC细胞过程; 2）如果Hh和Wnt 通路通过抑制magu和dlp的表达来阻止GSC后代中的BMP信号传导; 3）间隙如何 连接维持EC细胞过程-生殖细胞粘附并控制GSC后代分化。因为 控制干细胞分化的分子机制对于提供功能性细胞以 细胞疗法，防止癌症干细胞扩增，减缓衰老，从中获得的知识 这项研究对于治疗人类退行性疾病以及对抗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，因此这项研究的结果将有助于 也有助于更好地了解人类生殖生物学。

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.