Astrocyte Transcriptional Dependencies in Brain Circuits

Project Summary Over the past twenty years our knowledge of astrocytes has undergone a renaissance highlighted by the identification of dynamic physiological activities, key roles in circuit function, and diverse molecular properties. Central to the physiological activities of every cell are transcription factors (TFs), yet roles for TFs in mature astrocyte function and associated circuits in the brain have remained relatively undefined. Our molecular studies on astrocyte diversity highlighted the expression of developmental TFs in mature astrocytes, in the adult brain. Among these TFs are members of the Nuclear Factor I (NFI)- and Sox- family, which play essential roles in early astrocyte development and continue to be expressed in a vast majority of mature astrocytes throughout the adult brain. Despite exhibiting universal expression in astrocytes across all regions, we found that NFIA and Sox9 exhibit region specific roles in mature astrocytes, where hippocampal astrocytes require NFIA to maintain their functional integrity, while olfactory bulb astrocytes require Sox9. Our finding that astrocytes exhibit region specific transcriptional dependencies, where at given TF is absolutely essential for function in one region, but is dispensable in other regions, serves as the foundational observation for this R35 application. We will use other NFI- and Sox- family TF members that are universally expressed in astrocytes to map region-specific transcriptional dependencies across the developing, adult, and aging brain. Our analysis will be comprehensive, spanning core astrocyte functions, interactions with neurons, and circuit-level activities. We posit that these region-specific transcriptional dependencies for astrocyte function will provide an entry point for understanding how astrocyte diversity is encoded. Therefore, we will use a host of transcriptomic, epigenomic, and proteomic approaches to uncover how these regional-specific TF functions are conferred, while functionalizing roles for key downstream target genes. Finally, astrocyte dysfunction is associated with a host of neurodegenerative diseases, including Alzheimer’s Disease. Here, we will apply our findings and new mouse models to AD, seeking to uncover how these core features of astrocyte TF function contribute to AD disease pathogenesis.