Stem Cell Renewal and Differentiation in Spermatogenesis

 描述（由申请人提供）：对指导干细胞行为的电路有浓厚的兴趣。在我们的许多组织中，这些干细胞调节回路由容纳干细胞的壁龛控制。还不清楚小生境是如何在组织中被指定和组装的，以及它是如何对干细胞库进行控制的。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 利用了一个最广为人知的干细胞生态位系统，果蝇睾丸。在这里，一小群细胞（枢纽细胞）充当生态位的一部分，导致邻近细胞中信号通路的激活。以这种方式，附近的体细胞承担囊肿干细胞命运（CySC），而与这些CySC混合的附近的生殖系细胞承担生殖系干细胞命运（GSC）。重要的是，这两种不同的干细胞类型必须协调其子细胞的产生，以使精子发生正常发生。在上一个融资周期中，我们在利基组装和利基功能的实时成像方面取得了根本性的突破.在这里，我们利用这一前所未有的分辨率来解决利基组装和功能的基础机制。枢纽的形成和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细胞（SGPs）中的定位和定位产生了一个前锚定的增殖中心，它将以极化的方式驱动精子发生。为了产生这种极性，前枢纽细胞的子集必须对定位线索做出反应。然而，这些线索及其来源目前都不清楚。本提案旨在定义这些线索及其工作方式。在我们的许多组织中，壁龛容纳多种干细胞类型，就像果蝇睾丸壁龛一样。因此，为了维持组织，必须协调多种常驻干细胞类型的行为。然而，我们在任何情况下都不知道如何。这项建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.