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.

维持体组织功能需要干细胞适应性地响应 生理信号和分化，同时通过调节 平静和自我更新。海马齿状回亚区放射状胶质样神经干细胞的研究 成年海马产生齿状颗粒细胞和星形胶质细胞，这一过程被称为 成年海马神经发生神经干细胞必须平衡长期维持与 需要响应不同的生理信号的分化和扩展。这些 基本的决定是由小生境信号控制的，这些信号在细胞内招募细胞自主因子， 成体海马神经干细胞尽管越来越多的研究已经开始 成年海马神经干细胞调控相关转录因子的鉴定 静止与不对称自我更新，转录因子的身份，耦合 成年海马（或成年大脑）中静止和对称自我更新的调节 在很大程度上是未知的。在这里，我们将测试中心假设，Kruppel样因子9（Klf 9）， 锌指转录因子，有助于长期维持和神经干细胞 通过调节静止和对称干细胞在成年海马中的扩增 分裂为了实现这一目标，我们将建立在我们广泛的初步数据， 工程化的条件Klf 9敲除和mCherry敲入融合小鼠，群体和克隆 谱系追踪和纵向活体双光子成像 体内干细胞执行拟议的目标将为理解奠定基础 神经干细胞中Klf 9水平如何通过调节 通过控制对称自我更新的快速动员和扩张的静止， 成人大脑从这一提案中获得的见解可以指导补充/扩大 在不同的疾病状态下， 老化和受伤后。