Control of Stem Cell Fate in Drosophila Spermatogenesis

描述（由申请人提供）：尽管精原干细胞对生殖至关重要，但其调控机制尚不清楚。环境、遗传和表观遗传因素对干细胞的建立、维持和功能至关重要，但在哺乳动物系统中系统地识别这些因素极具挑战性。因此，大多数干细胞在其自然组织微环境或生态位中的行为尚不清楚。然而，了解干细胞-生态位相互作用对于开发成功的基于干细胞的治疗方法至关重要。我们使用果蝇精子发生作为模型系统，因为它与哺乳动物系统相似，但我们可以精确地定位干细胞并从基因上操纵它们的生态位。先前的资助使我们能够发现控制果蝇睾丸干细胞更新的分子机制。干细胞附着在一小群被称为中枢的体细胞支持细胞上，中枢分泌一种配体，激活相邻细胞中的janus -激酶信号转换器和转录激活因子（Jak-STAT）信号，指示它们保持干细胞的状态。从中心移开的子体是有区别的。在这些发现的基础上，在这次更新中，我们将描述我们最近发现的干细胞维持这个生态位所需的其他因素，并确定它们在这个过程中是否与Jak-STAT信号通路一起起作用。这包括使用遗传和生化方法的结合来评估1)染色质重塑复合体和2)激素信号通路在精原干细胞更新中的作用。我们还将确定受Jak-STAT信号调控的其他基因，然后使用遗传学方法确定它们在正常和老年生态位中的作用。总之，这项工作将为调控干细胞维持的遗传和表观遗传机制提供基本的见解。

DESCRIPTION (provided by applicant): Although spermatogonial stem cells are essential for reproduction, their regulation is poorly understood. Environmental, genetic and epigenetic factors are crucial for stem cell establishment, maintenance, and function, but systematically identifying these factors is extremely challenging in mammalian systems. Consequently, the behavior of most stem cells within their natural tissue microenvironments, or niches, is not well-understood. However, understanding stem cell-niche interactions is critical for developing successful stem cell-based therapeutic approaches. We use Drosophila spermatogenesis as a model system, since it parallels mammalian systems, yet we can precisely locate the stem cells and manipulate their niche genetically. Prior funding enabled us to discover the molecular mechanism controlling stem cell renewal in the Drosophila testis. Stem cells adhere to a small cluster of somatic support cells called the hub, which secretes a ligand that activates Janus-kinase-signal transducer and activator of transcription (Jak-STAT) signaling in adjacent cells, instructing them to remain as stem cells. Daughters displaced away from the hub differentiate. Building on these findings, in this renewal we will characterize additional factors we have recently found to be required for stem cell maintenance in this niche, and determine if they act together with the Jak-STAT signaling pathway during this process. This includes using a combination of genetic and biochemical approaches to assess the role of 1) chromatin remodeling complexes and 2) hormonal signaling pathways in spermatogonial stem cell renewal. We will also identify additional genes regulated by Jak-STAT signaling then use genetic approaches to determine their roles in both normal and aged niches. Together this work will provide fundamental insight into the genetic and epigenetic mechanisms that regulate stem cell maintenance.