Stem Cell Renewal and Differentiation in Spermatogenesis

 描述(由申请者提供)：人们对引导干细胞行为的回路非常感兴趣。在我们的许多组织中，这些干细胞调节电路由容纳干细胞的缝隙控制。目前还不清楚这个利基是如何在组织中指定和组装的，以及它是如何控制干细胞库的。了解这些相互作用对于干细胞在再生医学中的应用至关重要。这项建议 利用了最广为人知的干细胞-壁龛系统之一--果蝇睾丸。在这里，一小群细胞(中枢细胞)作为利基的一部分，导致相邻细胞中信号通路的激活。通过这种方式，附近的体细胞承担着孢子干细胞的命运(CySC)，而附近的生殖系细胞与这些CySCs混合在一起，承担着生殖系干细胞的命运(GSC)。重要的是，这两种不同类型的干细胞必须协调它们的子代细胞的产生，才能正常地发生精子发生。在上一个资金周期中，我们在实时成像方面取得了根本性突破，无论是利基组装还是利基功能。在这里，我们利用这一史无前例的决心来处理作为利基组合和运作基础的机制。中枢的形成和随之而来的干细胞的附着是性腺发生的主要结构事件。中枢细胞在体细胞性腺前体(SGPS)之间的指定和放置产生一个向前锚定的增殖中心，该中心将以极化的方式驱动精子发生。要产生这种极性，前中枢单元的子集必须对定位提示做出反应。然而，这些线索和它们的来源目前都不清楚。这项提案寻求定义这些线索以及它们如何发挥作用。在我们的许多组织中，壁龛包含多种干细胞类型，就像果蝇睾丸的壁龛一样。因此，为了维持组织，多种驻留干细胞类型的行为必须协调一致。然而，在任何情况下，我们都不知道是如何做到的。这项提议将解决这一基本问题。

 DESCRIPTION (provided by applicant): There is intense interest in the circuits that guide stem cell behavior. In many of our tissues, these stem cell regulatory circuits are controlled by the niches that house the stem cells. it is not understood how the niche is specified and assembled in a tissue, and then how it executes control over the stem cell pool. Understanding these interactions will be crucial to the use of stem cells in regenerative medicine. This proposal utilizes one of the most well-understood stem cell-niche systems, the Drosophila testis. Here, a small group of cells (hub cells) act as part of the niche, leading to the activation of signaling pathways in adjacent cells. In this way, nearby somatic cells take on cyst stem cell fate (CySC), while nearby germline cells, intermingled with these CySCs, take on germline stem cell fate (GSC). Importantly, these two distinct stem cell types must coordinate their production of daughter cells for spermatogenesis to occur properly. Over the last funding cycle, we made fundamental breakthroughs in live- imaging both niche assembly and niche function. Here, we capitalize on this unprecedented level of resolution to tackle the mechanisms that underlie niche assembly and function. Hub formation, and the attendant attachment of stem cells, is the major architectural event of gonadogenesis. The specification and placement of hub cells among somatic gonadal precursors (SGPs) generates an anteriorly-anchored proliferation center that will drive spermatogenesis in a polarized manner. To generate that polarity, a subset of pre-hub cells must respond to positioning cues. However, neither those cues nor their source are currently known. This proposal seeks to define those cues and how they work. In many of our tissues, niches house multiple stem cell types, just as does the Drosophila testis niche. Thus, to maintain tissues the behavior of the multiple resident stem cell types must be coordinated. However, in no case do we understand how. This proposal will address this essential question.