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: 9354502
• 负责人: Erika L Matunis
• 金额: $ 37.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9354502
• 关键词: Adult; Affect; Age; Aging; Alpha Cell; Automobile Driving; Biological Assay; Biological Models; Cell Adhesion; Cell Lineage; Cell Maintenance; Cells; Child; Clonal Expansion; DNA Polymerase II; Data; Daughter; Disease; Drosophila genus; Dwarfism; Ensure; Fathers; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Future Generations; Gene Expression Profiling; Generations; Genes; Genetic; Genetic Screening; Genome; Germ Cells; Hereditary Disease; Homologous Gene; Human; Individual; Janus kinase; Learning; Link; Maintenance; Malignant Neoplasms; Mammals; Masculine; Modeling; Molecular; Mus; Mutation; Natural regeneration; Organism; Ovarian; Ovary; Paternal Age; Process; Protein Tyrosine Kinase; Ras Signaling Pathway; Regenerative Medicine; Regulation; Reproduction; Role; STAT protein; Signal Pathway; Signal Transduction; Spermatogenesis; Stem cells; Supporting Cell; System; Testing; Testis; Time; Tissues; Transcription Repressor/Corepressor; Work; adult stem cell; age effect; cell type; fly; genetic approach; genome-wide; genome-wide analysis; germline stem cells; high risk; in vivo; male; man; member; men; neuronal cell body; next generation; offspring; sertoli cell; sex; sex determination; sperm cell; stem cell biology; stem cell differentiation; stem cell division; stem cell fate; stem cell niche; tissue regeneration; tool; transdifferentiation

Abstract Adult stem cells regenerate tissue by dividing asymmetrically, producing both new stem cells and differentiating daughters. Spermatogonial stem cells provide a lifetime supply of sperm in organisms ranging from flies to man. Like all germline stem cells, they uniquely transmit the genome to future generations. Signals from specialized local microenvironments (or niches) regulate stem cells in general, but in most tissues niches are difficult to identify and manipulate in vivo. An exception is the Drosophila testis, which is a leading model for stem cell biology. In this tissue, local Janus-kinase-signal transducer and activator of transcription (Jak-STAT) signaling promotes stem cell renewal within a well-defined niche, while cells exiting the niche differentiate. In our prior work, characterization of STAT targets led us to discover that an individual stem cell can acquire a mutation that gives it a competitive advantage: as a result, that cell and its progeny can displace all of the neighboring (wild-type) stem cells from the niche over time. This phenomenon, called stem cell competition, has intriguing but unproven connections to human reproduction. Older fathers have a higher risk of having children with genetic defects such as dwarfism that are caused by rare, dominant activating mutations in signaling pathway components. Although the mutations are bad for the offspring, they are thought to be are selected for in aging men because they give individual spermatogonial stem cells a competitive advantage. Since stem cell competition has not been observed directly in mammals and is not understood mechanistically, in Aim 1 we characterize this process in depth using the Drosophila testis, which offers genetic approaches that surpass those available in mammals, and should inform the understanding of stem cell competition quite generally. In addition to controlling stem cell competition, niche signals also ensure that stem cells in the adult Drosophila testis maintain their “male” identity. Sex maintenance, which is a type of stem cell transdifferentiation, occurs in mammals but is not well understood mechanistically. Therefore, in Aim 2 we combine genome-wide analysis of gene expression with genetic tools unique to Drosophila to learn how sex maintenance is regulated in vivo. This will advance the field of regenerative medicine and continue to expand our understanding of spermatogonial stem cells - the cornerstone of male reproduction.

抽象的 成年干细胞通过不对称分裂，再生的组织，产生两个新的干细胞 和区分女儿。精子干细胞在 从苍蝇到人的生物。像所有种系干细胞一样，它们独特地传输 基因组到子孙后代。来自专业当地微环境（或壁ni）的信号 通常，调节干细胞，但在大多数组织中，小生态位很难识别和操纵 体内。果蝇睾丸是一个例外，它是干细胞生物学的主要模型。在 该组织，局部的Janus-激酶信号传感器和转录激活因子（JAK-STAT） 信号传导促进了定义明确的小众内部的干细胞更新 区分。在我们先前的工作中，统计目标的表征使我们发现 单个干细胞可以获取具有竞争优势的突变：结果， 该细胞及其后代可以将所有相邻的（野生型）干细胞置换 随着时间的推移。这种现象称为干细胞竞争，有吸引力但未经证实的 与人类繁殖的联系。年长的父亲有生育孩子的风险更高 遗传缺陷，例如矮人，是由罕见的，主要的激活突变引起的 信号通路组件。尽管突变对后代有害，但它们是 被认为是在老年男性中选择的，因为它们给了个体的精子茎 细胞具有竞争优势。由于尚未直接观察到干细胞竞争 哺乳动物，并且不了解机械理解，在AIM 1中，我们深入表征了这个过程 使用果蝇睾丸，提供的遗传方法超过了那些可用的方法 哺乳动物，应该一般都可以告知对干细胞竞争的理解。在 除了控制干细胞竞争，小众信号还确保了干细胞中的干细胞 成年果蝇睾丸保持其“男性”身份。性维护，这是一种茎 细胞转分化发生，发生在哺乳动物中，但机械上没有很好地理解。 因此，在AIM 2中，我们将基因表达全基因组分析与遗传工具相结合 果蝇独有的知识是如何在体内调节性别维持。这将推动 再生医学领域，并继续扩展我们对精子的理解 干细胞 - 男性繁殖的基石。