Neurotransmitter signaling controls 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 必须在动物的一生中保持健康的、不同种类的干细胞库，同时还产生 最佳组织功能所必需的分化子细胞。受控制的班次变化由 促进自我更新而不是分化的特定信号可能被用于损伤后的组织修复 或预防衰老症状。相反，持续的不平衡会导致肿瘤等异常状态。 当自我更新被看好时形成，或当分化是主要结果时干细胞丢失。定义 因此，决定干细胞命运的分子机制是当务之急。 在这里，我们研究了苍蝇卵巢中的上皮性卵泡干细胞(FSCs)利用经典 神经递质信号决定自我更新与分化命运。在最近的工作中，我们 证明轴突样投射从FSCS延伸出来，以响应摄食，形成相互作用的网 跨越利基市场。通过轴突调节器静止体(SIF， TIAM-1)和疾病(NAV2)导致发育缺陷，更重要的是，破坏了细胞命运的平衡 指示自我更新或分化的标记。预测增长取决于Hedgehog(HH)信号， 转录激活剂Cubutus Interruptus(Ci)是延伸所必需的。推论词的转录 因此，目标可能对调解FSC预测与其目标(其他)之间的沟通至关重要 FSCS或生殖细胞)，我们定义了FSCS在3小时后的时间点发生的基因表达变化 喂食。拟议中的工作集中在一组高度丰富的基因上，这些基因具有已知的神经肌肉功能。 连接突触，以及FSC命运由GABA/谷氨酸平衡决定的模型 发信号。非神经干细胞通过神经递质信号进行交流的想法可能适用 到其他干细胞系统，强调我们对时空功能的精确分子解剖 候选监管机构可能会发现一种新的基本机制来调控干细胞的命运。

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.