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 成体干细胞通过不对称分裂来再生组织，产生两种新的干细胞 精原干细胞提供终生的精子供应。 像所有生殖干细胞一样，它们独特地传播从果蝇到人类的生物体。 来自特定局部微环境（或生态位）的基因组信号。 一般而言，调节干细胞，但在大多数组织中，很难识别和操纵干细胞 一个例外是果蝇睾丸，它是干细胞生物学的主要模型。 该组织，局部 Janus 激酶信号转导器和转录激活子 (Jak-STAT) 信号传导促进干细胞在明确定义的生态位内更新，而细胞则退出该生态位 在我们之前的工作中，STAT 目标的表征使我们发现 单个干细胞可以获得赋予其竞争优势的突变：因此， 该细胞及其后代可以从生态位中取代所有邻近的（野生型）干细胞 随着时间的推移，这种被称为干细胞竞争的现象很有趣，但尚未得到证实。 年长的父亲生出患有此类疾病的孩子的风险更高。 遗传缺陷，例如侏儒症，是由罕见的显性激活突变引起的 虽然这些突变对后代不利，但它们是信号通路的组成部分。 人们认为它们被选用于老年男性，因为它们赋予个体精原干 由于干细胞竞争尚未直接观察到。 哺乳动物，不能机械地理解，在目标 1 中，我们深入描述了这个过程 使用果蝇睾丸，它提供了超越现有方法的遗传方法 哺乳动物，并且应该能够相当普遍地理解干细胞竞争。 除了控制干细胞竞争外，生态位信号还确保干细胞在 成年果蝇睾丸维持其“雄性”身份，这是茎的一种。 细胞转分化发生在哺乳动物中，但其机制尚不清楚。 因此，在目标 2 中，我们将基因表达的全基因组分析与遗传工具结合起来 了解果蝇体内性别维持的独特机制，这将推动果蝇的发展。 再生医学领域并不断扩大我们对精原细胞的了解 干细胞 - 男性生殖的基石。