Regulation of astrocyte diversity in the cerebellum

小脑星形胶质细胞多样性的调节

• 批准号: 10454433
• 负责人: TOMASZ K KORDULA
• 金额: $ 46.03万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454433
• 关键词: AMPA Receptors; Adult; Affect; Agreement; Architecture; Astrocytes; Biology; Birth; Blood - brain barrier anatomy; Brain; Brain region; Calcium; Cell Differentiation process; Cells; Cerebellum; Characteristics; Chromatin; Chromatin Loop; Communication; DNA Binding; Data; Development; Epigenetic Process; Fibrous Astrocyte; Gap Junctions; Gene Expression; Genes; Glial Fibrillary Acidic Protein; Gliosis; Hypertrophy; Ion Channel; Knockout Mice; Messenger RNA; Microglia; Modification; Molecular; Morphology; Motor Skills; Mus; Myeloid Cells; Neuroglia; Neurons; Neurotransmitters; Normal Statistical Distribution; Oligodendroglia; Pattern; Play; Process; Program Sustainability; Purkinje Cells; Regulation; Resolution; SHH gene; Slide; Subgroup; Synapses; Testing; Translating; YY1 Transcription Factor; Yin-Yang; astrocyte progenitor; astrogliosis; differential expression; experimental study; histone modification; in vivo; insight; motor deficit; nerve stem cell; neuroepithelium; neuronal circuitry; novel; novel strategies; postnatal; progenitor; programs; recruit; relating to nervous system; single-cell RNA sequencing; synaptogenesis; transcription factor; white matter

Astrocytes are extremely diverse across different brain regions and perform specialized function. Diversity of these cells is generated by initial patterning and then promoted by region- specific communication with neurons to fine-tune astrocytes to the local requirements. While important insights have been gained into the diversity of astrocytes using novel approaches, molecular mechanisms controlling their diversity remain mostly elusive. In the cerebellum, astrocytes differentiate into highly specialized Bergmann glia of the molecular layer, velate astrocytes of the granular cell layer, and fibrous astrocytes of the white matter. This proposal aims at understanding mechanisms that regulate diverse astrocyte subpopulations in the cerebellum. Our results strongly suggest that a transcription factor, Yin Yang 1 (YY1), is essential for sustaining the distinct functions of astrocyte subpopulations in both the developing and the adult cerebellum. Deletion of YY1 in cerebellar astrocytes manifests in contrasting effects in the molecular layer versus the granular cell layer and white matter by post-natal day 20. We found astrogliosis in the molecular layer associated with GFAP+ astrocyte hypertrophy and loss of typical morphology whereas the numbers of GFAP+ astrocytes in the granular cell layer and white matter were drastically diminished. Furthermore, we found that YY1 differentially alters gene expression at the later stages of astrocyte development in a region-specific manner and is continuously needed in mature astrocytes. To test the hypothesis that YY1-dependent chromatin architecture is critical to execute and sustain programs that affect functions of diverse astrocyte subpopulations in the cerebellum, we will: 1. Establish the effects of YY1 on the major functions of subpopulations of cerebellar astrocytes, and 2. Obtain insights into the molecular mechanisms by which YY1 regulates subpopulations of cerebellar astrocytes.

星形胶质细胞在不同的大脑区域是非常多样化的， 功能这些细胞的多样性是由初始模式产生的，然后由区域促进- 与神经元的特异性通信，以微调星形胶质细胞以满足局部需求。而 使用新的方法已经获得了对星形胶质细胞多样性的重要认识， 控制其多样性的分子机制大多仍然难以捉摸。在小脑中， 星形胶质细胞分化为分子层高度特化的Bergmann胶质细胞， 颗粒细胞层的星形胶质细胞和白色物质的纤维星形胶质细胞。这项建议旨在 在理解调节小脑中不同星形胶质细胞亚群的机制方面。 我们的研究结果有力地表明，转录因子阴阳1（YY 1），是必要的， 维持发育中和成人中星形胶质细胞亚群的独特功能 小脑在小脑星形胶质细胞中YY 1的缺失表现出在脑胶质细胞中的对比效应。 出生后第20天，分子层与颗粒细胞层和白色物质。我们发现 与GFAP+星形胶质细胞肥大相关的分子层中的星形胶质细胞增生和典型的 颗粒细胞层和白色物质中GFAP+星形胶质细胞的数量 急剧减少。此外，我们发现YY 1差异改变基因表达， 在星形胶质细胞发育的后期阶段以区域特异性的方式， 在成熟的星形胶质细胞中。为了验证YY 1依赖的染色质结构 是执行和维持影响不同星形胶质细胞功能程序的关键 在小脑的亚群，我们将：1。确定YY 1对主要功能的影响 小脑星形胶质细胞的亚群，和2.深入了解分子机制 YY 1通过其调节小脑星形胶质细胞的亚群。