Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity.
Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity.
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作者：
Hanamsagar R;Alter MD;Block CS;Sullivan H;Bolton JL;Bilbo SD
有证据表明，当正常的神经发育轨迹被破坏时，即当电路或细胞没有达到完全成熟状态时，许多神经系统疾病就会出现。小胶质细胞在正常的神经发育中起着关键作用，并被假设为导致脑部疾病。我们使用全转录组分析和纯化的发育中的小胶质细胞的下一代测序来鉴定小胶质细胞发育基因表达程序，该程序涉及数千个基因，其表达水平在发育过程中单调变化（上升或下降）。重要的是，雄性小鼠的基因表达程序相对于雌性小鼠延迟，成年雄性小鼠暴露于LPS（一种有效的免疫激活剂）加速了雄性小鼠的小胶质细胞发育。接下来，将从纯化的小鼠小胶质细胞获得的基因表达模式产生的小胶质细胞发育指数（MDI）应用于人脑转录组数据集，以测试小胶质细胞发育的变异性与人类疾病（如阿尔茨海默氏症和自闭症）相关的假设，其中小胶质细胞被认为发挥作用。MDI在阿尔茨海默病和自闭症中均显著增加，这表明加速的小胶质细胞发育可能有助于神经病理学。总之，我们在小鼠中确定了一种小胶质细胞特异性基因表达程序，用于创建小胶质细胞发育指数，该指数应用于包含异质细胞类型的人类数据集，以揭示健康和患病大脑样本之间以及男性和女性之间的差异。这种强大的工具具有广泛的适用性，可以在疾病的背景下检查小胶质细胞的发育，并响应其他变量，如压力和药物治疗。
Evidence suggests many neurological disorders emerge when normal neurodevelopmental trajectories are disrupted, i.e. when circuits or cells do not reach their fully mature state. Microglia play a critical role in normal neurodevelopment and are hypothesized to contribute to brain disease. We used whole transcriptome profiling with Next Generation sequencing of purified developing microglia to identify a microglial developmental gene expression program involving thousands of genes whose expression levels change monotonically (up or down) across development. Importantly, the gene expression program was delayed in males relative to females and exposure of adult male mice to LPS, a potent immune activator, accelerated microglial development in males. Next, a microglial developmental index (MDI) generated from gene expression patterns obtained from purified mouse microglia, was applied to human brain transcriptome datasets to test the hypothesis that variability in microglial development is associated with human diseases such as Alzheimer’s and autism where microglia have been suggested to play a role. MDI was significantly increased in both Alzheimer’s Disease and in autism, suggesting that accelerated microglial development may contribute to neuropathology. In conclusion, we identified a microglia-specific gene expression program in mice that was used to create a microglia developmental index, which was applied to human datasets containing heterogeneous cell types to reveal differences between healthy and diseased brain samples, and between males and females. This powerful tool has wide ranging applicability to examine microglial development within the context of disease and in response to other variables such as stress and pharmacological treatments.
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影响因子：
15.1
作者：
Oskvig, Devon B.;Elkahloun, Abdel G.;Johnson, Kory R.;Phillips, Terry M.;Herkenham, Miles
通讯作者：
Herkenham, Miles
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
11
作者：
Canetta S;Bolkan S;Padilla-Coreano N;Song LJ;Sahn R;Harrison NL;Gordon JA;Brown A;Kellendonk C
通讯作者：
Kellendonk C
影响因子：
6.2
作者：
Schafer, Dorothy P.;Lehrman, Emily K.;Stevens, Beth
通讯作者：
Stevens, Beth
DOI：
10.1016/j.jsbmb.2015.09.039
发表时间：
2016-06
期刊：
The Journal of steroid biochemistry and molecular biology
影响因子：
--
作者：
Hanamsagar R;Bilbo SD
通讯作者：
Bilbo SD