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：
10278047
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/10278047
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 Structure of molecular layer of cerebellar cortex 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

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非常多样化，并且执行专业功能。这些细胞的多样性是通过初始图案产生的，然后通过区域促进与神经元的特定沟通以微调星形胶质细胞，以满足当地需求。尽管使用新颖的方法，重要的见解已经获得了星形胶质细胞的多样性，控制其多样性的分子机制仍然难以捉摸。在小脑中，星形胶质细胞分化为分子层的高度专业化的伯格曼神经胶质颗粒细胞层的星形胶质细胞和白质的纤维星形胶质细胞。该提议的目的了解调节小脑中各种星形胶质细胞亚群的机制。我们的结果强烈表明，转录因子阳阳1（yy1）对于维持发展中心和成人的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的缺失在对比的影响中表现到产后第20天，分子层与颗粒细胞层和白质。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多和典型的丧失形态学，而颗粒细胞层和白质中GFAP+星形胶质细胞的数量急剧减少。此外，我们发现YY1差异改变了基因表达在星形胶质细胞发育的后期以特定区域的方式发展，并且是连续的需要成熟的星形胶质细胞。检验YY1依赖性染色质结构的假设对影响各种星形胶质细胞功能的程序执行和维持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的亚群和2。 YY1调节小脑星形胶质细胞的亚群。