Astrocyte Transcriptional Dependencies in Brain Circuits

项目摘要 在过去的二十年里，我们对星形胶质细胞的认识经历了一次复兴， 动态生理活动的鉴定，电路功能中的关键作用，以及不同的分子特性。 每个细胞的生理活动的中心是转录因子（TF），然而TF在成熟细胞中的作用是不确定的。 星形胶质细胞的功能和脑中的相关回路仍然相对不明确。我们的分子 对星形胶质细胞多样性的研究强调了发育TF在成熟星形胶质细胞中的表达， 成人大脑在这些转录因子中，有核因子I（NFI）和Sox家族的成员，它们在转录过程中起着至关重要的作用。 在早期星形胶质细胞发育中的作用，并继续在绝大多数成熟星形胶质细胞中表达 在成年人的大脑中。尽管在所有区域的星形胶质细胞中表现出普遍表达，我们发现 NFIA和Sox 9在成熟星形胶质细胞中表现出区域特异性作用，其中海马星形胶质细胞需要 NFIA维持其功能完整性，而嗅球星形胶质细胞需要Sox9。 我们发现星形胶质细胞表现出区域特异性转录依赖性，在给定的TF是 在一个地区的功能是绝对必要的，但在其他地区是不可或缺的，作为基础， 这是R35的应用。我们将使用其他NFI和Sox家族TF成员， 在星形胶质细胞中表达，以绘制发育中，成人和成年人的区域特异性转录依赖性， 老化的大脑我们的分析将是全面的，涵盖核心星形胶质细胞功能，与神经元的相互作用， 和电路级活动。我们认为星形胶质细胞的这些区域特异性转录依赖性 功能将为理解星形胶质细胞多样性是如何编码的提供一个切入点。因此，我们将使用 一系列转录组学、表观基因组学和蛋白质组学方法来揭示这些区域特异性TF 功能被赋予，同时功能化关键下游靶基因的作用。最后，星形胶质细胞 功能障碍与许多神经退行性疾病有关，包括阿尔茨海默病。这里我们 将我们的发现和新的小鼠模型应用于AD，寻求揭示星形胶质细胞的这些核心特征是如何 TF功能参与AD的发病机制。

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.