Regulation of astrocyte diversity in the cerebellum

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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.