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Regulation of astrocyte diversity in the cerebellum

小脑星形胶质细胞多样性的调节

基本信息

批准号：
10659171
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
项目类别：
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/10659171
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 Proliferating 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 neural neuroepithelium neuronal circuitry novel novel strategies postnatal progenitor programs recruit single-cell RNA sequencing synaptogenesis transcription factor white matter

项目摘要

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极其多样化，并执行专门的功能。这些细胞的多样性是通过最初的图案化产生的，然后通过区域- 与神经元进行特定的交流，以微调星形胶质细胞以适应局部需求。而当使用新的方法对星形胶质细胞的多样性有了重要的见解，控制它们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质的纤维性星形胶质细胞。这项提议旨在了解小脑中不同星形胶质细胞亚群的调节机制。我们的结果有力地表明，转录因子阴阳1(YY1)是在发育和成人中维持星形胶质细胞亚群的不同功能小脑。小脑星形胶质细胞中YY1的缺失在在出生后第20天，分子层与颗粒细胞层和白质的对比。我们发现分子层星形胶质细胞增生症与GFAP+星形胶质细胞肥大及典型的而颗粒细胞层和白质中GFAP阳性星形胶质细胞的数量已经大大减少了。此外，我们还发现YY1基因差异地改变了基因的表达在星形胶质细胞发育的后期，以一种区域特有的方式，并持续成熟的星形胶质细胞所需要的。检验依赖于YY1的染色质结构的假设对执行和维持影响不同星形胶质细胞功能的程序至关重要小脑中的亚群，我们将：1.建立YY1对主要功能的影响小脑星形胶质细胞亚群，以及2.深入了解分子机制 YY1通过其调节小脑星形胶质细胞亚群。