Stem Cell Renewal and Differentiation in Spermatogenesis

描述（由申请人提供）： 人们对指导干细胞行为的电路有着浓厚的兴趣。由于难以识别组织中的干细胞，大多数工作集中在控制干细胞的内在作用因子上，或者集中在识别允许其扩增同时保持其未分化状态的培养条件上。因此，对构成干细胞自然生态位的微环境知之甚少，尽管它提供了许多控制干细胞基本特性的信号。了解小生境-干细胞相互作用对于解开在再生医学中使用这些细胞所必需的电路至关重要。最为人所熟知的干细胞生态位系统之一是果蝇睾丸，因为干细胞和它们的生态位被精确地定义，并且调控程序的轮廓已经就位。睾丸小生境维持生殖系干细胞和体干细胞（分别为GSC和SSC）。在这里，两个重要的SSC因素，线和zfh-1，集中在，他们的研究使我们重新考虑的规则，这个完善的干细胞生态位模型。这个建议从概念上解决了干细胞生态位生物学的重要方面。首先，很少有系统可以高分辨率地研究在发育过程中区分干细胞和其小生境细胞的遗传电路。目的1A旨在确定线和它的伙伴蛋白质碗在介导的SSC-小生境的命运选择在性腺发育中的作用。由于神经干细胞也可以产生其小生境的细胞，因此对这里确定的电路的兴趣将很高。第二，Hedgehog信号转导与包括癌症干细胞在内的各种干细胞类型的维持有关，但Hh信号转导赋予干细胞的特定特征仍然难以捉摸。目的1B旨在确定Hh在SSCs中的作用，特别是评估干细胞的哪些定义特征受Hh信号转导的调节。第三，了解抑制干细胞分化的机制是再生医学许多工作的主要目标。目的2A试图确定Zfh-1阻断体细胞分化并赋予体细胞干细胞特性的机制。目的2A试图定义Zfh-1如何与GSC中的STAT活化（非自主地）合作。Aim 2C提出了互补的方法来识别Zfh-1控制下的基因，以帮助完成这两项任务。前景也很好，我们的工作可以从根本上促进干细胞生物学的这一方面。 公共卫生相关性：人们对指导干细胞行为的电路有着浓厚的兴趣。了解小生境-干细胞相互作用对于解开在再生医学中使用这些细胞所必需的电路至关重要。这个建议从概念上解决了干细胞生态位生物学的重要方面。

DESCRIPTION (provided by applicant): There is intense interest in the circuits that guide stem cell behavior. Due to the difficulty in identifying stem cells in tissues, most work has centered on intrinsically-acting factors that control stem cells, or on identifying culture conditions that allow their expansion while yet maintaining their undifferentiated state. Thus, there is significantly less known about the microenvironment that comprises a stem cell's natural niche, even though it provides many of the signals that govern fundamental stem cell properties. Understanding niche-stem cell interactions is central to unraveling the circuitry necessary to use these cells in regenerative medicine. One of the most well-understood stem cell-niche systems is the Drosophila testis, because the stem cells and their niche are precisely defined and the outlines of a regulatory program are in place. The testis niche maintains both germline and somatic stem cells (GSCs and SSCs, respectively). Here, two essential SSC factors, lines and zfh-1, are focused upon, and their study has led us to a reconsideration of the rules governing this well-established stem cell-niche model. This proposal addresses conceptually significant facets of stem cell-niche biology. First, there are precious few systems where one can at high resolution investigate the genetic circuitry that discriminates a stem cell from its niche cell during development. Aim 1A seeks to define the role of lines and its partner protein bowl in mediating SSC-niche fate choice in gonadogenesis. Since a neural stem cell can also generate cells of its niche, interest in the circuitry identified here will be high. Second, Hedgehog signaling has been implicated in the maintenance of various stem cell types, including cancer stem cells, but the particular characteristics that Hh signaling assigns to stem cells have remained elusive. Aim 1B seeks to define the role of Hh in SSCs, in particular, assessing which of the defining characteristics of stem cells are regulated by Hh signaling. Third, understanding the mechanisms that repress differentiation in stem cells is a major goal of much work in regenerative medicine. Aim 2A seeks to identify the mechanism whereby Zfh-1 blocks differentiation and confers stem cell properties to somatic cells. Aim 2A seeks to define how Zfh-1 cooperates (non-autonomously) with STAT activation in GSCs. Aim 2C proposes complementary approaches to identify genes under Zfh-1 control that help accomplish both of these tasks. The prospects are also excellent that our work can contribute in a fundamental manner to this aspect of stem cell biology. Public Health Relevance: There is intense interest in the circuits that guide stem cell behavior. Understanding niche-stem cell interactions is central to unraveling the circuitry necessary to use these cells in regenerative medicine. This proposal addresses conceptually significant facets of stem cell-niche biology.