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.

维持躯体组织功能需要干细胞适应性地对 生理信号和分化，同时确保自我保护通过调节 宁静和自我更新。大鼠齿状回亚区的放射状胶质细胞样神经干细胞 成年海马体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。神经干细胞必须在长期维护和 对不同生理信号的分化和扩增的需求。这些 基本决策由利基信号控制，这些信号在内部招募细胞自主因子 成年海马神经干细胞。尽管越来越多的研究已经开始 鉴定偶联成年海马神经干细胞调控的转录因子 静止与不对称自我更新，即耦合的转录因子的身份 成人海马区(或成人脑)的静止和对称性自我更新的调节 在很大程度上是未知的。在这里，我们将检验中心假设，即类Kruppel因子9(Klf9)， 一种锌指转录因子，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区的扩张 组织。为了实现这一目标，我们将以我们广泛的初步数据为基础，新聘 工程化条件性KLF9基因敲除和mCherry基因敲入融合小鼠，群体和克隆 个体成年海马神经的谱系追踪和纵向双光子成像 体内的干细胞。执行拟议的目标将为理解 神经干细胞中Klf9水平如何通过调节 通过控制对称自我更新来实现快速动员和扩展的静止 成人的大脑。从这项提案中收集的见解可能会指导战略，以补充/扩大 神经干细胞库和在不同疾病状态下恢复海马回路的可塑性， 衰老和损伤后。