State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
Cell Prolif. 2023 Sep;56(9):e13439. doi: 10.1111/cpr.13439. Epub 2023 Mar 6.
Microglia are the primary source of transglutaminase 2 (TGM2) in the brain; however, the roles of microglial TGM2 in neural development and disease are still not well known. The aim of this study is to elucidate the role and mechanisms of microglial TGM2 in the brain. A mouse line with a specific knockout of Tgm2 in microglia was generated. Immunohistochemistry, Western blot and qRT-PCR assays were performed to evaluate the expression levels of TGM2, PSD-95 and CD68. Confocal imaging, immunofluorescence staining and behavioural analyses were conducted to identify phenotypes of microglial TGM2 deficiency. Finally, RNA sequencing, qRT-PCR and co-culture of neurons and microglia were used to explore the potential mechanisms. Deletion of microglial Tgm2 causes impaired synaptic pruning, reduced anxiety and increased cognitive deficits in mice. At the molecular level, the phagocytic genes, such as Cq1a, C1qb and Tim4, are significantly down-regulated in TGM2-deficient microglia. This study elucidates a novel role of microglial TGM2 in regulating synaptic remodelling and cognitive function, indicating that microglia Tgm2 is essential for proper neural development.
小胶质细胞是脑中转谷氨酰胺酶 2（TGM2）的主要来源；然而，小胶质细胞 TGM2 在神经发育和疾病中的作用仍不清楚。本研究旨在阐明小胶质细胞 TGM2 在大脑中的作用和机制。生成了一种在小胶质细胞中特异性敲除 Tgm2 的小鼠品系。通过免疫组织化学、Western blot 和 qRT-PCR 检测来评估 TGM2、PSD-95 和 CD68 的表达水平。通过共聚焦成像、免疫荧光染色和行为分析来鉴定小胶质细胞 TGM2 缺乏的表型。最后，通过 RNA 测序、qRT-PCR 和神经元与小胶质细胞共培养来探索潜在机制。小胶质细胞 Tgm2 的缺失导致小鼠突触修剪受损、焦虑减轻和认知缺陷增加。在分子水平上，TGM2 缺陷型小胶质细胞中的吞噬基因，如 Cq1a、C1qb 和 Tim4，显著下调。这项研究阐明了小胶质细胞 TGM2 在调节突触重塑和认知功能中的新作用，表明小胶质细胞 Tgm2 对于正常的神经发育是必不可少的。
