CONTROL OF STEM CELL FATE IN DROSOPHILA SPERMATOGENESIS

描述：（从申请人的摘要扫描）精子发生依赖于 睾丸内干细胞群的建立和维持。 虽然精原干细胞对生殖是必不可少的， 了解他们的规则。来自附近细胞的环境信号被认为 对干细胞的维持至关重要，但识别它们是极其困难的。 在哺乳动物系统中具有挑战性。果蝇精子发生提供了 研究干细胞调节的极好模型系统，因为精原细胞 干细胞可以被识别，遗传学可以被系统地用于 鉴定调节分子。在这项建议中，高度重视 干细胞维持中保守的Jak-STAT信号转导通路是 考察Jak激酶同源物Hopscotch（Hop）是干细胞增殖所必需的。 维持，Jak-Stat信号通路的过度激活导致 具有干细胞特征的异位细胞。此外，激活Jak-STAT的配体是 存在于一小群体细胞中，称为枢纽， 细胞被锚定。这导致了以下假设：座包括股骨柄 细胞龛，或专门的局部环境，指示附近的细胞， 通过激活这些细胞内的Jak-STAT通路来保留干细胞的命运。 为了验证这一假设，Jak-STAT信号转导在小生境中的确切作用 将被审查。在目标1中，将产生标记的功能丧失克隆， 确定干细胞是否直接需要Jak-STAT信号。在目标2中， Jak-Stat信号分子的功能丧失和异位表达将 测试Jak-STAT信号是否指示干细胞命运，或者， 需要允许干细胞存活。在目标3中，Jak-STAT的作用 将研究限制小生境中干细胞数量的信号传导。最后， 因为其他因素可能与Jak-STAT协同作用， 在维持干细胞生态位之后，我们采用遗传学方法， 在目标4中系统地确定这些因素的方法。自从果蝇 和哺乳动物精子发生是保守的， 本提案中所揭示的内容可能会增加对 调节干细胞驻留在更复杂和更少定义 环境，如哺乳动物精原干细胞，这是必不可少的 对人类生育能力的影响

DESCRIPTION: (Scanned from the applicant's abstract) Spermatogenesis relies on the establishment and maintenance of a stem cell population within the testis. Although spermatogonial stem cells are essential for reproduction, little is known about their regulation. Environmental cues from nearby cells are thought to be crucial for stem cell maintenance, but identifying them is extremely challenging in mammalian systems. Drosophila spermatogenesis provides an excellent model system for studying stem cell regulation, since spermatogonial stem cells can be identified, and genetics can be used to systematically identify regulatory molecules. In this proposal the role of the highly conserved Jak-STAT signal transduction pathway in stem cell maintenance is examined. The Jak kinase homologue Hopscotch (Hop) is required for stem cell maintenance, and overactivation of the Jak-Stat signaling pathway leads to ectopic cells with stem cell character. Also, the ligand activating Jak-STAT is present in a small group of somatic cells, called the hub, to which the stem cells are anchored. This leads to the hypothesis that the hub comprises a stem cell niche, or specialized local environment, that instructs nearby cells to retain a stem cell fate by activating the Jak-STAT pathway within these cells. To test this hypothesis, the precise role of Jak-STAT signaling in the niche will be examined. In Aim 1, marked loss-of-function clones will be generated to determine if stem cells directly require Jak-STAT signaling. In Aim 2, both loss-of-function and ectopic expression of Jak-Stat signaling molecules will test whether Jak-STAT signaling instructs stem cell fate or, alternatively, is required to permit stem cell viability. In Aim 3, the role of Jak-STAT signaling in limiting stem cell numbers in the niche will be studied. Finally, since it is likely that other factors act either in concert with Jak-STAT, or subsequent to it in maintaining the stem cell niche, we employ genetic approaches to systematically identify these factors in Aim 4. Since Drosophila and mammalian spermatogenesis are conserved, the regulatory mechanisms uncovered in this proposal will likely add to the understanding of the regulation of stem cells residing in more complex and less defined environments, such as mammalian spermatogonial stem cells, which are essential for human fertility.