Uncovering mechanisms controlling germline stem cell competition

项目摘要 控制干细胞自我更新、竞争和分化的分子机制对干细胞的生长和分化具有重要意义。 在癌症治疗、再生医学和干细胞疗法方面的进展潜力。干 细胞存在于一种特殊的、静止的微环境中，这种微环境被称为小生境， 促进常驻干细胞的维持。关于是什么调节了自主的 每种干细胞类型内的行为。然而，对它们的竞争行为知之甚少， 干细胞之间的关系果蝇睾丸是研究干细胞的最佳范例之一 行为在这个组织中，一个静止的小生境支持两个干细胞群： 这些细胞包括产生精子的GSC（GSC）和产生囊细胞的体细胞囊干细胞（CySC）。先前工作 已经表明，GSC在利基市场上相互竞争有限的空间，但人们对GSC知之甚少。 控制这种协同性的分子机制。这个提议揭示了第一个赋予一个 雄性GSC具有胜过其野生型邻居并定殖睾丸干细胞小生境的能力。的 本申请的初步数据显示，果蝇睾丸中的竞争性GSC及其后代 通过改变生态位环境使它们的野生型邻居处于不利地位。此外，具有竞争力的GSC仍然 通过上调粘附因子免疫这些改变。果蝇的复杂遗传技术 将用于实现本建议中的目标。Aim 1的重点是转录调控， 竞争性GSC中的细胞外基质因子。目标2将测试竞争性全球供应链拥有的模型 增加的粘附力，从而使它们保持在生态位中，而它们的野生型邻居分化。我们 设想这项工作将影响人类生殖生物学和再生医学。

Project Summary The molecular mechanisms controlling stem cell self-renewal, competition and differentiation hold great potential for advances in treating cancer, and in regenerative medicine and in stem cell-based therapies. Stem cells reside in specialized, quiescent microenvironments called niches that secrete short-range signals promoting the maintenance of resident stem cells. Much is known about what regulates the autonomous behaviors within each stem cell type. However, much less is known about the competitive behaviors of between stem cells. The Drosophila testis is one of the best characterized paradigms for investigating stem cell behavior. In this tissue, a single quiescent niche supports two stem cell populations: germline stem cells (GSCs), which give rise to sperm, and somatic cyst stem cells (CySCs), which produce cyst cells. Prior work has shown that GSCs compete with each other for limited space at the niche, but little is known about molecular mechanisms controlling this cooperativity. This proposal reveals the first mutation that endows a male GSC with the ability to out-compete its wild-type neighbors and colonize the testis stem cell niche. The preliminary data in this application show that a competitive GSC and its descendants in the Drosophila testis disadvantage their wild-type neighbors by altering the niche milieu. Additionally, the competitive GSCs remain immune to these alterations by upregulating adhesion factors. Sophisticated genetic techniques in Drosophila will be used to achieve the aims in this proposal. Aim 1 is focused on the transcriptional regulation of extracellular matrix factors in competitive GSCs. Aim 2 will test the model that competitive GSCs have increased adhesion, thus allowing them to remain in the niche while their wild-type neighbors differentiate. We envision this work will impact human reproductive biology and regenerative medicine.