Transcriptional Control of adult hippocampal neural stem cell homeostasis

成人海马神经干细胞稳态的转录控制

• 批准号: 10201930
• 负责人: Amar Sahay
• 金额: $ 50.78万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201930
• 关键词: Adult; Aging; Animals; Astrocytes; Brain; Brain Diseases; Cell Count; Cell Maintenance; Cells; Clone Cells; Coupled; Data; Disease; Engineering; Ensure; Equilibrium; Exhibits; Foundations; Genetic; Glean; Goals; Hippocampus (Brain); Image; Individual; Injury; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Label; Maintenance; Mediating; Molecular; Mus; Mutation; Neuroglia; Pattern; Photons; Physiological; Population; Process; Proteins; Protocols documentation; Radial; Regulation; Reporter; Signal Transduction; Structure; Testing; Time; Tissues; Transcriptional Regulation; Trees; Ventricular; Zinc Fingers; dentate gyrus; granule cell; in vivo; insight; loss of function; nerve stem cell; neurogenesis; neuroregulation; overexpression; preservation; prevent; progenitor; recruit; relating to nervous system; response; satellite cell; self-renewal; stem; stem cell differentiation; stem cell division; stem cell homeostasis; stem cells; transcription factor

Maintenance of somatic tissue functions necessitates stem cells to adaptively respond to physiological signals and differentiate while ensuring self-preservation through regulation of quiescence and self-renewal. Radial glia-like neural stem cells in the dentate gyrus subregion of the adult hippocampus give rise to dentate granule cells and astrocytes, a process referred to as adult hippocampal neurogenesis. Neural stem cells must balance long-term maintenance with demands for differentiation and expansion in response to distinct physiological signals. These fundamental decisions are governed by niche-signals that recruit cell-autonomous factors within adult hippocampal neural stem cells. Although a growing number of studies have begun to identify transcription factors that couple the regulation of adult hippocampal neural stem cell quiescence with asymmetric self-renewal, the identities of transcription factors that couple regulation of quiescence and symmetric self-renewal in the adult hippocampus (or adult brain) are largely not known. Here, we will test the central hypothesis that Kruppel-like factor 9 (Klf9), a zinc finger transcription factor, contributes to long-term maintenance and neural stem cell expansion in the adult hippocampus through regulation of quiescence and symmetric stem cell divisions. Towards this goal, we will build on our extensive preliminary data employing newly engineered conditional Klf9 knock out and mCherry knock-in fusion mice, population and clonal lineage tracing, and longitudinal live 2 photon imaging of individual adult hippocampal neural stem cells in vivo. Execution of the proposed Aims will establish a foundation for understanding how Klf9 levels in neural stem cells balance long-term preservation through regulation of quiescence with rapid mobilization and expansion through control of symmetric self-renewal in the adult brain. Insights gleaned from this proposal may guide strategies to replenish/expand the pool of neural stem cells and restore hippocampal circuit plasticity in different disease states, aging and following injury.

维持体细胞功能需要干细胞适应性反应 生理信号和区分，同时通过调节来确保自我保护 静止和自我更新。 radial胶质神经胶质样神经干细胞在齿状回的齿状回区域 成年海马产生齿状颗粒细胞和星形胶质细胞，这一过程称为 成人海马神经发生。神经干细胞必须与长期维持之间的平衡 响应不同生理信号的分化和扩展的需求。这些 基本决定由利基信号支配，这些信号在 成年海马神经干细胞。尽管越来越多的研究开始 识别成年海马神经干细胞调节的转录因子 与不对称自我更新的静止，转录因子的身份 在成年海马（或成年大脑）中的静止和对称自我更新的调节 在很大程度上不知道。在这里，我们将测试中心假设，即Kruppel样因子9（KLF9）， 锌指转录因子有助于长期维持和神经干细胞 通过调节静脉和对称干细胞的成年海马扩展 部门。为了实现这一目标，我们将以新的初步数据为基础 有条件的有条件的KLF9敲门和MCHERRY敲门融合小鼠，种群和克隆 谱系跟踪和纵向活体2光子成年海马神经成像 干细胞在体内。执行拟议的目标将为理解建立基础 神经干细胞中的KLF9水平如何通过调节来平衡长期保存 通过控制对称自我更新的快速动员和扩展的静止 成人大脑。从该提案中收集的见解可能指导策略补充/扩展 神经干细胞的池并恢复不同疾病状态下的海马电路可塑性， 衰老和受伤后。