Novel Hexb-based tools for studying microglia in the CNS
Novel Hexb-based tools for studying microglia in the CNS
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DOI：
10.1038/s41590-020-0707-4
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发表时间：
2020-06-15
影响因子：
30.5
通讯作者：
Prinz, Marco
中科院分区：
文献类型：
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作者：
Masuda, Takahiro;Amann, Lukas;Prinz, Marco
小胶质细胞在中枢神经系统（CNS）疾病和稳态中起着关键作用，但对其研究可能具有挑战性。Prinz及其同事鉴定出氨基己糖苷酶β亚基（Hexb）由小胶质细胞特异性表达，并且即使在炎症条件下也稳定。小胶质细胞和中枢神经系统（CNS）相关巨噬细胞（CAM），如血管周围和脑膜巨噬细胞，几乎涉及所有CNS疾病。然而，很少有人知道他们的细胞类型特异性的作用，在没有合适的工具，将允许个体发育密切相关的小胶质细胞和CAM之间的功能歧视。为了开发新的小胶质细胞基因靶向模型，我们首先应用大规模平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，并将氨基己糖苷酶亚基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在病理过程中大幅下调。接下来，我们产生了Hexb（tdTomato）小鼠来稳定地监测体内小胶质细胞的行为。最后，theHexblocus用于小胶质细胞中他莫昔芬诱导的Cre介导的基因操作，以及小胶质细胞（但不包括CAM）的命运绘图。总之，我们提供了有价值的新的遗传工具，专门研究小胶质细胞在中枢神经系统中的功能。
Microglia have key roles in central nervous system (CNS) disease and homeostasis but their study can be challenging. Prinz and colleagues identify hexosaminidase subunit beta (Hexb) to be specifically expressed by microglia and stable even under inflammatory conditions.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 generatedHexb(tdTomato)mice to stably monitor microglia behavior in vivo. Finally, theHexblocus 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.