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.

摘要 成体干细胞通过不对称分裂再生组织，产生新的干细胞， 和区分女儿。精原干细胞提供精子的终身供应， 从苍蝇到人类的生物体。像所有的生殖系干细胞一样，它们独特地传递 基因组给后代。来自特定局部微环境（或小生境）的信号 一般来说，它可以调节干细胞，但在大多数组织中，小生境很难识别和操纵。 in vivo.一个例外是果蝇睾丸，这是干细胞生物学的主要模型。在 局部Janus激酶信号转导和转录激活因子（Jak-STAT） 信号传导促进干细胞在明确的小生境内更新，而细胞离开小生境 区分。在我们之前的工作中，STAT靶点的表征使我们发现， 单个干细胞可以获得一种突变， 该细胞及其后代可以取代所有邻近的（野生型）干细胞 随着时间这种现象被称为干细胞竞争， 与人类生殖的联系。年龄较大的父亲有更高的风险有孩子与 遗传缺陷，如侏儒症，是由罕见的，显性激活突变， 信号传导通路组件。虽然突变对后代是有害的， 被认为是在老年男性中选择的，因为它们提供了单独的精原干细胞。 细胞的竞争优势。由于干细胞竞争尚未直接观察到， 哺乳动物和不理解机械，在目标1中，我们深入描述了这一过程 使用果蝇睾丸，它提供了遗传方法，超过了现有的方法， 哺乳动物，并应告知相当普遍的干细胞竞争的理解。在 除了控制干细胞竞争外，小生境信号还确保了干细胞在体内的生长。 成年果蝇睾丸保持其“雄性”身份。性维持，这是一种茎 细胞转分化发生在哺乳动物中，但在机制上还没有很好的理解。 因此，在目标2中，我们将联合收割机基因表达的全基因组分析与遗传工具相结合 了解果蝇体内如何调节性维持。这将推动 再生医学领域，并继续扩大我们对精原细胞的理解 干细胞-男性生殖的基石。