Distinct phases of adult microglia proliferation: a Myc-mediated early phase and a Tnfaip3-mediated late phase.
Distinct phases of adult microglia proliferation: a Myc-mediated early phase and a Tnfaip3-mediated late phase.
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DOI：
10.1038/s41421-022-00377-3
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发表时间：
2022-04-12
期刊：
影响因子：
33.5
通讯作者：
Guan, Zhonghui
中科院分区：
文献类型：
--
作者：
Tan, Wulin;Su, Po-Yi Paul;Leff, Jacqueline;Gao, Xiang;Chen, Jiao;Guan, Andrew K.;Kalyanasundaram, Gokul;Ma, Averil;Guan, Zhonghui
小胶质细胞增生是许多神经系统疾病的标志，包括阿尔茨海默病、中风、癫痫、创伤性脑和脊髓损伤以及周围神经和视神经损伤。最近的研究表明，新的自我更新的小胶质细胞具有特定的神经功能。然而，成人小胶质细胞增殖的机制仍不清楚。在这里，通过单细胞 RNA 测序、流式细胞术和免疫组织化学，我们证明坐骨神经损伤诱导了小鼠脊髓中小胶质细胞增殖的两个不同阶段，每个阶段都有不同的基因表达谱。我们证明，神经损伤后脊髓小胶质细胞中的转录因子 Myc 短暂上调，介导早期小胶质细胞增殖。另一方面，我们发现肿瘤坏死因子α诱导蛋白3（Tnfaip3）下调以介导不依赖Myc的晚期小胶质细胞增殖。我们发现细胞周期蛋白依赖性激酶 1（一种在细胞周期 M 期具有重要功能的激酶）仅参与早期阶段。我们发现，尽管早期阶段对于晚期增殖既不是必要的也不是充分的，但晚期阶段抑制了脊髓中早期小胶质细胞的增殖。最后，我们证明脊髓小胶质细胞增殖的终止需要 Myc 和 Tnfaip3 恢复其基线表达。因此，我们描绘了分化小胶质细胞增殖中的交互式信号网络。
Microgliosis is a hallmark of many neurological diseases, including Alzheimer’s disease, stroke, seizure, traumatic brain and spinal cord injuries, and peripheral and optic nerve injuries. Recent studies have shown that the newly self-renewed microglia have specific neurological functions. However, the mechanism of adult microglia proliferation remains largely unclear. Here, with single-cell RNA sequencing, flow cytometry, and immunohistochemistry, we demonstrate that the sciatic nerve injury induced two distinct phases of microglia proliferation in mouse spinal cord, each with different gene expression profiles. We demonstrate that the transcription factor Myc was transiently upregulated in spinal cord microglia after nerve injury to mediate an early phase microglia proliferation. On the other hand, we reveal that the tumor-necrosis factor alpha-induced protein 3 (Tnfaip3) was downregulated to mediate the Myc-independent late-phase microglia proliferation. We show that cyclin dependent kinase 1, a kinase with important function in the M phase of the cell cycle, was involved only in the early phase. We reveal that although the early phase was neither necessary nor sufficient for the late phase proliferation, the late-phase suppressed the early phase microglia proliferation in the spinal cord. Finally, we demonstrate that the termination of spinal cord microglia proliferation required both Myc and Tnfaip3 to resume their baseline expression. Thus, we have delineated an interactive signaling network in the proliferation of differentiated microglia.
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耦合的增殖和凋亡维持成人大脑中小胶质细胞的快速离职。
影响因子：
8.8
作者：
Askew K;Li K;Olmos-Alonso A;Garcia-Moreno F;Liang Y;Richardson P;Tipton T;Chapman MA;Riecken K;Beccari S;Sierra A;Molnár Z;Cragg MS;Garaschuk O;Perry VH;Gomez-Nicola D
通讯作者：
Gomez-Nicola D
影响因子：
16.2
作者：
Bohlen CJ;Bennett FC;Tucker AF;Collins HY;Mulinyawe SB;Barres BA
通讯作者：
Barres BA
影响因子：
25
作者：
Ajami, Bahareh;Bennett, Jami L.;Rossi, Fabio M. V.
通讯作者：
Rossi, Fabio M. V.
影响因子：
64.5
作者：
Keren-Shaul, Hadas;Spinrad, Amit;Amit, Ido
通讯作者：
Amit, Ido
影响因子：
5.5
作者：
Guimaraesi, Rafaela M.;Davoli-Ferreira, Marcela;Cunha, Thiago M.
通讯作者：
Cunha, Thiago M.