Regulation of astrocyte diversity in the cerebellum

星形胶质细胞在不同的大脑区域中极其多样化，并且执行专门的任务 功能。这些细胞的多样性是通过初始模式产生的，然后通过区域促进 与神经元的特定通信，以根据局部需求微调星形胶质细胞。同时 使用新方法对星形胶质细胞的多样性获得了重要的见解， 控制其多样性的分子机制仍然大多难以捉摸。在小脑中， 星形胶质细胞分化为分子层高度特化的伯格曼神经胶质细胞 颗粒细胞层的星形胶质细胞和白质的纤维星形胶质细胞。该提案旨在 了解调节小脑中不同星形胶质细胞亚群的机制。 我们的结果强烈表明转录因子 Yin Yang 1 (YY1) 对于 维持发育中和成人星形胶质细胞亚群的独特功能 小脑。小脑星形胶质细胞中 YY1 的缺失在 到出生后第 20 天，分子层与颗粒细胞层和白质的对比。我们发现 与 GFAP 星形胶质细胞肥大和典型星形胶质细胞丧失相关的分子层星形胶质细胞增生 形态，而颗粒细胞层和白质中 GFAP 星形胶质细胞的数量 都急剧减少。此外，我们发现 YY1 差异性地改变基因表达 在星形胶质细胞发育的后期阶段，以区域特定的方式持续进行 成熟的星形胶质细胞需要。检验 YY1 依赖性染色质结构的假设 对于执行和维持影响不同星形胶质细胞功能的程序至关重要 小脑亚群中，我们将： 1. 确定 YY1 对主要功能的影响 小脑星形胶质细胞亚群的组成，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。

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.