Development and molecular phenotypes of zebrafish astrocytes

斑马鱼星形胶质细胞的发育和分子表型

• 批准号: 9916366
• 负责人: Kelly R Monk
• 金额: $ 42.35万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916366
• 关键词: Animal Model; Animals; Astrocytes; Biological Assay; Biological Models; Biology; Blood - brain barrier anatomy; Blood Vessels; Brain; CRISPR/Cas technology; Cell Communication; Cell physiology; Cells; Characteristics; Complex; Development; Developmental Biology; Event; Exhibits; Fibroblast Growth Factor Receptors; Foundations; Functional disorder; Genes; Glutamate Transporter; Growth; Growth and Development function; Health; Homeostasis; Human; Individual; Investigation; Knowledge; Label; Larva; Mammals; Mediating; Membrane; Mental disorders; Methods; Molecular; Molecular Genetics; Morphogenesis; Morphology; Nerve Degeneration; Nervous system structure; Neuraxis; Neurites; Neuroglia; Neurologic; Neurons; Optics; Pattern; Physiology; Play; Preparation; Process; Radial; Reporter; Reporting; Resolution; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Spinal Cord; Study models; Synapses; System; Testing; Work; Zebrafish; base; bone; cell type; experimental study; extracellular; gene function; genetic approach; in vivo; insight; migration; molecular phenotype; mouse model; nerve stem cell; nervous system development; nervous system disorder; neural circuit; postnatal; promoter; spatiotemporal; synaptogenesis; tool

Astrocytes are the major glial cell type in the human brain and are critical for central nervous system (CNS) development and function. Astrocyte dysfunction has been implicated in human neurodevelopmental and psychiatric diseases. Given the important roles astrocytes play in CNS development and health, it is surprising that little is known about the molecular and cellular mechanisms that govern astrocyte maturation and their functional interactions with neighboring cells. One caveat for currently available model systems is the inability to manipulate and observe astrocyte development and dynamic changes in living, intact animals. Transparent zebrafish larvae would be ideally suited for such studies, but bone fide astrocytes have not been described in this system to date. Here, we aim to exploit the optical transparency of zebrafish larvae together with molecular and genetic approaches to characterize a new glial cell type in zebrafish that features key hallmarks of mammalian astrocytes. We have identified a previously unreported cell type in zebrafish CNS with several defining characteristics of mammalian astrocytes, such as intricate bushy morphology, glutamate transporter expression, and spontaneous microdomain Ca2+ transients. In this proposal, we will: 1) fully characterize the development and function of astrocytes in zebrafish; 2) develop a cell-specific CRISPR/Cas9 method to study astrocyte biology in vivo. We expect our work will establish zebrafish as a new model system to explore astrocyte development and function, provide new insights into the molecular and cellular mechanisms regulating astrocyte development and growth, and lay the foundation to study astrocyte function in the context of the entire nervous system in an intact and behaving animal.

星形胶质细胞是人脑中主要的神经胶质细胞类型，对中枢神经系统 (CNS) 至关重要 发育和功能。星形胶质细胞功能障碍与人类神经发育和 精神疾病。鉴于星形胶质细胞在中枢神经系统发育和健康中发挥的重要作用，令人惊讶 对于控制星形胶质细胞成熟及其作用的分子和细胞机制知之甚少 与邻近细胞的功能相互作用。当前可用模型系统的一个警告是无法 操纵和观察活体完整动物中星形胶质细胞的发育和动态变化。透明的 斑马鱼幼虫非常适合此类研究，但真正的星形胶质细胞尚未在 该系统迄今为止。在这里，我们的目标是利用斑马鱼幼虫的光学透明度以及分子 和遗传方法来表征斑马鱼中的一种新的神经胶质细胞类型，其特征是 哺乳动物星形胶质细胞。我们在斑马鱼中枢神经系统中发现了一种以前未报道的细胞类型，其中有几种 哺乳动物星形胶质细胞的定义特征，例如复杂的浓密形态、谷氨酸转运蛋白 表达和自发微区 Ca2+ 瞬变。在本提案中，我们将：1）充分描述 斑马鱼星形胶质细胞的发育和功能； 2）开发细胞特异性的CRISPR/Cas9方法进行研究 星形胶质细胞体内生物学。我们期望我们的工作将斑马鱼建立为一个新的模型系统来探索 星形胶质细胞的发育和功能，为分子和细胞机制提供新的见解 调控星形胶质细胞的发育和生长，为研究星形胶质细胞的功能奠定基础 完整且有行为能力的动物的整个神经系统。