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: 9155328
• 负责人: Erika L Matunis
• 金额: $ 37.51万
• 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/9155328
• 关键词: Adult; Affect; Age; Aging; 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; Generations; Genes; Genetic; Genetic Screening; Genome; Hereditary Disease; Homologous Gene; Human; Individual; Janus kinase; Learning; Left; Life; Link; Maintenance; Malignant Neoplasms; Mammals; Modeling; Molecular; Mus; Mutation; Natural regeneration; Organism; Ovarian; Ovary; Paternal Age; Process; Protein Tyrosine Kinase; 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; abstracting; 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 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