CONTROL OF STEM CELL FATE IN DROSOPHILA SPERMATOGENESIS

果蝇精子发生中干细胞命运的控制

• 批准号: 6784235
• 负责人: Erika L Matunis
• 金额: $ 12.34万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784235
• 关键词: DNA binding protein; Drosophilidae; JAK kinase; biological signal transduction; cell cycle; cell growth regulation; cell population study; developmental genetics; enzyme activity; enzyme inhibitors; gene expression; germ cells; ligands; mutant; spermatogenesis; stem cells; testis

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.

描述：（从申请人的摘要中扫描）精子发生依赖于 睾丸内干细胞群的建立和维持。 尽管精原干细胞对于生殖至关重要，但其作用却很少。 了解他们的监管。人们认为来自附近细胞的环境线索 对于干细胞的维持至关重要，但识别它们极其困难 在哺乳动物系统中具有挑战性。果蝇的精子发生提供了 自精原细胞以来，研究干细胞调节的优秀模型系统 干细胞可以被识别，并且遗传学可以用于系统地 识别调节分子。在这项提案中，高度重视的角色 干细胞维持中保守的 Jak-STAT 信号转导通路是 检查了。干细胞需要 Jak 激酶同源物 Hopscotch (Hop) Jak-Stat 信号通路的维持和过度激活会导致 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，称为中枢，干细胞位于其中 细胞被锚定。这导致了轮毂包括茎的假设 细胞生态位，或特殊的局部环境，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。 为了检验这一假设，Jak-STAT 信号在利基中的精确作用 将接受检查。在目标 1 中，将生成标记的功能丧失克隆 确定干细胞是否直接需要 Jak-STAT 信号传导。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命运，或者是否是 需要允许干细胞存活。在目标 3 中，Jak-STAT 的作用 将研究限制微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，或者 在维持干细胞生态位之后，我们采用遗传 目标 4 中系统识别这些因素的方法。 和哺乳动物的精子发生是保守的，其调节机制 本提案中所涵盖的内容可能会增加对 干细胞的调控更加复杂且不明确 环境，例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。