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: 6536325
• 负责人: Erika L Matunis
• 金额: $ 17.3万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 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 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536325
• 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 睾丸中干细胞种群的建立和维护。 尽管精子干细胞对于繁殖至关重要，但几乎没有 知道他们的调节。认为附近细胞的环境提示 对于干细胞维护至关重要，但是识别它们非常 在哺乳动物系统中具有挑战性。果蝇的精子发生提供了 由于精子量，用于研究干细胞调节的出色模型系统 可以识别干细胞，遗传学可用于系统地 确定调节分子。在这个提议中，高度的角色 保守的JAK-STAT信号转导途径是干细胞维护中的 检查。干细胞需要JAK激酶同源物Hopscotch（HOP） 维护和过度激活JAK-STAT信号通路导致 异位细胞具有干细胞特征。另外，配体激活jak-stat是 存在于一小部分的体细胞中，称为轮毂，茎上 细胞是锚定的。这导致了一个假说，即轮毂包含一个茎 细胞生态位或专门的当地环境，指示附近的细胞 通过激活这些细胞内的JAK-Stat途径来保留干细胞命运。 为了检验这一假设，jak-stat信号在利基市场中的确切作用 将被检查。在AIM 1中，将生成明显的功能丧失克隆 确定干细胞是否直接需要JAK-STAT信号传导。在AIM 2中，两者都 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还是 允许干细胞生存能力所需。在AIM 3中，Jak-Stat的角色 将研究利基中限制干细胞数中的信号传导。最后， 由于其他因素可能与Jak-STAT一起起作用，或者 在维持干细胞生态位时，我们采用了遗传 在目标4中系统地识别这些因素的方法。因为果蝇 和哺乳动物的精子发生是保守的，是调节机制 在本提案中发现的可能会增加对 居住在更复杂且定义较低的干细胞的调节 环境，例如哺乳动物精子干细胞，这是必不可少的 用于人类生育。