Microglia and central nervous system (CNS)-associated macrophages (CAMs), such as perivascular and meningeal macrophages, are implicated in virtually all diseases of the CNS. However, little is known about their cell-type-specific roles in the absence of suitable tools that would allow for functional discrimination between the ontogenetically closely related microglia and CAMs. To develop a new microglia gene targeting model, we first applied massively parallel single-cell analyses to compare microglia and CAM signatures during homeostasis and disease and identified hexosaminidase subunit beta (Hexb) as a stably expressed microglia core gene, whereas other microglia core genes were substantially downregulated during pathologies. Next, we generated Hexb^tdTomato mice to stably monitor microglia behavior in vivo. Finally, the Hexb locus was employed for tamoxifen-inducible Cre-mediated gene manipulation in microglia and for fate mapping of microglia but not CAMs. In sum, we provide valuable new genetic tools to specifically study microglia functions in the CNS.

小胶质细胞和中枢神经系统 (CNS) 相关巨噬细胞 (CAM)，例如血管周围和脑膜巨噬细胞，与几乎所有 CNS 疾病有关。然而，在缺乏合适的工具来允许在个体遗传学密切相关的小胶质细胞和 CAM 之间进行功能区分的情况下，对它们的细胞类型特异性作用知之甚少。为了开发一种新的小胶质细胞基因靶向模型，我们首先应用大规模并行单细胞分析来比较稳态和疾病期间的小胶质细胞和 CAM 特征，并将己糖胺酶亚基 β ( Hexb)鉴定为稳定表达的小胶质细胞核心基因，而其他小胶质细胞核心基因是在病理期间显着下调。接下来，我们生成了Hexb ^tdTomato小鼠在体内稳定监测小胶质细胞的行为。最后，Hexb基因座被用于他莫昔芬诱导的 Cre 介导的小胶质细胞基因操作和小胶质细胞的命运图谱，但不用于 CAM。总之，我们提供了有价值的新遗传工具来专门研究中枢神经系统中的小胶质细胞功能。