Neurotransmitter signaling controls stem cell fate

神经递质信号控制干细胞命运

• 批准号: 10228794
• 负责人: Alana M O'Reilly
• 金额: $ 28.05万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228794
• 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; organizational structure; 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.

项目总结/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 必须在动物的一生中维持健康的、异质的干细胞库，同时还产生 最佳组织功能所必需的分化的子细胞。控制性转移由以下变化介导： 促进自我更新相对于分化的特异性信号可用于损伤后的组织修复 或预防衰老症状。相反，持续的失衡会导致异常状态，如肿瘤， 当自我更新是有利的，或干细胞损失时，分化是主要结果。限定 因此，迫切需要确定干细胞命运的分子机制。 在这里，我们调查了苍蝇卵巢中的上皮滤泡干细胞（FSC）利用经典的 神经递质信号传导来决定自我更新与分化的命运决定。在最近的工作中，我们 证明了轴突样突起从FSC中延伸出来，形成相互作用的网络， 跨越利基。通过轴突调节因子still life（sif， TIAM-1）和sickie（NAV 2）导致发育缺陷，重要的是，破坏细胞命运的平衡 指示自我更新或分化的标记。投射生长依赖于Hedgehog（Hh）信号传导， 转录激活因子Cubuitus Interruptus（Ci）是延伸所必需的。因此，Ci转录 因此，目标对于协调FSC预测与其目标（其他 FSC或生殖细胞），我们定义了FSC中发生的基因表达变化，在3小时的时间点后， 喂食拟议的工作集中在一组高度富集的基因上，这些基因在神经肌肉中具有已知的功能。 连接突触，以及FSC命运由GABA与谷氨酸的平衡决定的模型 发信号。非神经元干细胞通过神经递质信号传递的想法可能是适用的 其他干细胞系统，强调我们精确的分子解剖的时空功能， 候选监管者可能会发现一种新的调节干细胞命运的基本机制。