Mechanisms governing stem cell coordination by the niche

项目摘要/摘要 这项研究的广泛目标是了解多个干细胞群体 由利基控制以协调子代细胞的生产。成体干细胞之间的协调是 对维持组织动态平衡和防止肿瘤过度生长至关重要。许多结构，包括头发 卵泡、造血网和发育中的卵巢需要严格控制干细胞增殖和 从不同的干细胞谱系产生子代细胞的协调。在大多数情况下，分子 协调这种协调的机制在很大程度上是未知的。利用果蝇遗传学的力量 以及建立一个系统，对内源性利基内的干细胞进行纵向(20多小时)活体成像 我们已经开始揭示控制睾丸中干细胞协调的机制。体细胞干细胞 而睾丸的生殖系干细胞(GSCs)必须以精确的2：1比例产生子代，以便生殖细胞与 有效地分化成精子。我们的实时成像显示了GSCs中的一种修改的胞质分裂程序 仅在一个GSC子项与两个子项正确关联后才协调释放该子项的机制 体细胞干细胞谱系的。这个修改后的胞质分裂程序被控制在两个阶段--暂停 由来自小生境的Jak/STAT信号调节，并触发来自 体细胞干细胞。两个控制点都必须正确执行，否则干细胞胞质分裂失败 肿瘤形成，生殖细胞无法分化。虽然我们已经确定了停顿和 这些信号控制GSC胞质分裂的机制尚不清楚。此外， 胞体和生殖系沟通的程度，以确保产生适当比例的子代细胞 在很大程度上是未被开发的。这项研究使用分子遗传学和扩展的活体成像来询问特定的 NICE信号和体细胞联合调节GSC胞质分裂的机制 睾丸巢内干细胞之间的协调。通过建立一种对两个干细胞进行活体成像的方法 现在，我们还可以实时地直接可视化干细胞的协调并询问串扰 干细胞系之间的关系，这对组织的动态平衡至关重要。圆满完成拟议中的 这项工作将提供对干细胞-利基相互作用以及这些相互作用如何被破坏的重要洞察力 在肿瘤发生过程中，为未来的工作奠定了基础，旨在确定类似的机制在 其他组织和物种。

Project Summary / Abstract The broad objective of this study is to understand the mechanism by which multiple stem cell populations are controlled by the niche to coordinate daughter cell production. Coordination between adult stem cells is essential to maintain tissue homeostasis and prevent tumorous overgrowth. Many structures, including the hair follicle, hematopoietic network and developing ovary require tight control over stem cell proliferation and coordination of daughter cell production from distinct stem cell lineages. In most cases, the molecular mechanisms orchestrating this coordination are largely unknown. Leveraging the power of Drosophila genetics and establishing a system for longitudinal (20+ hours) live imaging of stem cells within an endogenous niche we have begun to reveal the mechanisms controlling stem cell coordination in the testis. Somatic stem cells and germline stem cells (GSCs) of the testis must generate daughters in a precise 2:1 ratio for germ cells to effectively differentiate into sperm. Our live imaging has revealed a modified cytokinesis program in GSCs as the mechanism to coordinate release of one GSC daughter only after it correctly associates with two daughters of the somatic stem cell lineage. This modified cytokinesis program is controlled at two stages—a pause regulated by Jak/STAT signaling from the niche and a trigger for completion of cytokinesis derived from the somatic stem cells. Both control points must be properly executed or stem cell cytokinesis fails, stem cell tumors form and germ cells fail to differentiate. While we have identified the source of both the pause and trigger, the mechanisms by which these signals control GSC cytokinesis remain unknown. In addition, the degree to which soma and germline communicate to ensure that proper ratios of daughter cells are produced is largely unexplored. This study uses molecular genetics and extended live imaging to interrogate the specific mechanisms by which niche signals and somatic stem cells combine to regulate GSC cytokinesis to ensure coordination between stem cells in the testis niche. By establishing a method for live imaging of both stem cell populations, we can now also directly visualize stem cell coordination in real time and interrogate the cross-talk between stem cell lineages that is essential for tissue homeostasis. Successful completion of the proposed work will provide significant insight into stem cell-niche interactions and how these may become disrupted during tumorigenesis, setting the foundation for future work aimed at identifying similar mechanisms at play in other tissues and species.