Neurotransmitter signaling controls stem cell fate

神经递质信号控制干细胞命运

• 批准号: 10386874
• 负责人: Alana M O'Reilly
• 金额: $ 23.38万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386874
• 关键词: Adhesions; Aging; Animals; Architecture; Axon; Cell Adhesion Molecules; Cell Cycle; Cells; Communication; Complex; Cyst; Defect; Dependence; Development; Differentiation Antigens; Dissection; Drosophila genus; Ensure; Epithelial; Equilibrium; Erinaceidae; Extracellular Matrix; Eye; Gene Expression; Genes; Genetic Transcription; Germ Cells; Glutamates; Goals; Growth; Health; Health Promotion; Hour; Injury; Integrin alpha Chains; Integrins; Internet; Lead; Lectin; Length; Life; Ligands; Maintenance; Mediating; Mind; Modeling; Molecular; Mutation; Neuromuscular Junction; Neurons; Neurotransmitter Receptor; Neurotransmitters; Nutrient; Organ; Ovary; Phase; Positioning Attribute; Prevention; Process; Proteins; Regulation; Role; Self-Direction; Signal Transduction; Structure; Symptoms; Synapses; System; Testing; Time; Tissues; Transcript; Transcription Coactivator; Work; axon growth; cell type; daughter cell; feeding; fly; gamma-Aminobutyric Acid; germline stem cells; glutamatergic signaling; prevent; primary outcome; protein complex; relating to nervous system; response; self-renewal; smoothened signaling pathway; spatiotemporal; stem cell fate; stem cell niche; stem cell proliferation; stem cell self renewal; stem cells; synaptogenesis; tissue repair; transcriptome; tumor

Project Summary/Abstract The equilibrium between stem cell self-renewal and differentiation is a cornerstone of tissue health. Stem cells must maintain healthy, heterogeneous stem cell pools throughout the lifetime of the animal, while also producing the differentiated daughter cells necessary for optimal tissue function. Controlled shifts mediated by changes in the specific signals that promote self-renewal versus differentiation may be leveraged for tissue repair after injury or prevention of aging symptoms. In contrast, continuous imbalance can lead to aberrant states such as tumor formation when self-renewal is favored, or stem cell loss when differentiation is the primary outcome. Defining the molecular mechanisms that determine stem cell fate is therefore a pressing need. Here, we investigate the possibility that epithelial Follicle Stem Cells (FSCs) in the fly ovary utilize classical neurotransmitter signaling to dictate self-renewal versus differentiation fate decisions. In recent work, we demonstrated that axon-like projections extend from FSCs in response to feeding, forming interactive webs that span the niche. Disruption of projection growth and interactions via mutation of the axon regulators still life (sif, TIAM-1), and sickie (NAV2) leads to developmental defects and, importantly, disrupts the balance of cell fate markers that instruct self-renewal or differentiation. Projection growth depends on Hedgehog (Hh) signaling, with the transcriptional activator Cubuitus Interruptus (Ci) necessary for extension. Reasoning that Ci transcriptional targets might thus be critical for mediating communication between FSC projections and their targets (other FSCs or germ cells), we defined the gene expression changes that occur in FSCs at 3 hours timepoints after feeding. The proposed work focused on a highly enriched set of genes with known functions at neuromuscular junction synapses, and the model that FSC fate is determined by the balance of GABA versus glutamate signaling. The idea that non-neuronal stem cells communicate via neurotransmitter signaling may be applicable to other stem cell systems, emphasizing that our precise molecular dissection of the spatio-temporal function of candidate regulators may uncover a new fundamental mechanism for regulation of stem cell fate.

项目摘要/摘要 干细胞自我更新和分化之间的平衡是组织健康的基石。干细胞 必须在动物的整个生命周期内保持健康的，异质的干细胞池 最佳组织功能所需的分化子细胞。受控的转移由变化介导 受伤后，可以利用促进自我更新与分化的特定信号用于组织修复 或预防衰老症状。相反，连续失衡会导致异常状态，例如肿瘤 当自我更新受到青睐时形成，或当分化是主要结果时的干细胞损失。定义 因此，确定干细胞命运的分子机制是一种紧迫的需求。 在这里，我们研究了卵巢中的上皮卵泡干细胞（FSC）利用经典的可能性 神经递质信号传导决定自我更新与分化命运决策。在最近的工作中，我们 证明类似轴突的预测从FSC响应于喂食而延伸，形成交互式网络 跨越利基。通过轴突调节剂静物的突变来破坏投影生长和相互作用（SIF， tiam-1），病态（NAV2）导致发育缺陷，重要的是，破坏了细胞命运的平衡 指导自我更新或差异化的标记。投影生长取决于刺猬（HH）信号，并具有 延伸所需的转录激活库中断（CI）。推理CI转录 因此，目标对于调解FSC预测及其目标之间的沟通可能至关重要（其他 FSC或生殖细胞），我们定义了FSC在FSC中的基因表达变化，在3小时后的时间点发生 进食。提出的工作着重于具有神经肌肉的高度富集基因集的高度富集基因 连接突触，以及FSC命运的模型由GABA与谷氨酸的平衡确定 信号。非神经干细胞通过神经递质信号传达的想法可能适用 到其他干细胞系统，强调我们的精确分子解剖 候选监管机构可能会发现调节干细胞命运的新基本机制。