CONTROL OF STEM CELL FATE IN DROSOPHILA SPERMATOGENESIS

描述：(摘自申请者摘要)精子发生依赖于 在睾丸内建立和维持干细胞群体。 尽管精原干细胞对生殖是必不可少的，但几乎不是 知道他们的规定。来自附近细胞的环境线索被认为是 对干细胞的维持至关重要，但识别它们是极其重要的 在哺乳动物系统中具有挑战性。果蝇精子发生提供了一种 研究干细胞调节的极佳模型系统，因为精原细胞 干细胞可以被识别，遗传学可以用来系统地 确定调节分子。在这项建议中，高度 干细胞维持中保守的Jak-STAT信号转导通路 检查过了。干细胞所需的Jak激酶同源物Hopscotch(Hop) Jak-Stat信号通路的维持和过度激活导致 具有干细胞特性的异位细胞。另外，激活Jak-Stat的配体是 存在于一小群被称为中枢的体细胞中，干细胞与之相连 细胞是固定的。这导致了轮毂由茎组成的假设 细胞生态位，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通路来维持干细胞的命运。 为了验证这一假设，Jak-STAT信号在利基中的确切作用 将会被检查。在目标1中，将生成标记的功能丧失克隆，以 确定干细胞是否直接需要JAK-STAT信号。在《目标2》中，两者 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的命运，或者 允许干细胞存活所需的。在目标3中，Jak-Stat的作用 在限制干细胞数量方面的信号将会被研究。最后， 因为很可能是其他因素与Jak-Stat协同作用，或者 在它维持干细胞生态位之后，我们使用了基因 在Aim中系统识别这些因素的方法4.自从果蝇 和哺乳动物的精子发生都是保守的，调控机制 这项提案中未涵盖的内容可能会增加对 驻留在更复杂和更不明确的环境中的干细胞的调控 环境，如哺乳动物精原干细胞，这是必不可少的 为了人类的生育能力。

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.