Brain milieu induces early microglial maturation through the BAX-Notch axis.
Brain milieu induces early microglial maturation through the BAX-Notch axis.
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大脑环境通过 BAX-Notch 轴诱导小胶质细胞早期成熟
DOI：
10.1038/s41467-022-33836-2
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发表时间：
2022-10-17
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
小胶质细胞来源于原始髓样细胞，并在胚胎脑中获得其早期身份。然而，脑环境赋予小胶质细胞成熟特征的机制仍然难以捉摸。在这里，我们证明了baxcq 55斑马鱼和baxtm 1 Sjk小鼠胚胎表现出类似的缺陷早期小胶质细胞成熟。BAX是一种典型的促凋亡因子，在神经细胞中高度富集，并通过促凋亡和非凋亡机制调节小胶质细胞的成熟。BAX通过CaMKII-CREB轴钙依赖性地调节活神经元中的dlb，同时确保凋亡神经元在迁移的前小胶质细胞中的有效Notch激活。Notch信号在支持胚胎小胶质细胞成熟中是保守的。在Cx 3cr 1Cre/+Rbpjfl/fl胚胎小鼠中发生受损的小胶质细胞发育;然而，当与DLL 3在体外孵育时，小胶质细胞获得其适当的特征。因此，我们的研究结果阐明了由小胶质细胞发育中的神经元环境触发的BAX-CaMKII-CREB-Notch网络，这可能为神经元疾病治疗中靶向小胶质细胞提供创新见解。大脑环境赋予小胶质细胞发育的机制尚不清楚。在这里，作者表明，由神经元环境触发的BAX-CaMKII-CREB-Notch信号轴在早期小胶质细胞成熟中起作用。
Microglia are derived from primitive myeloid cells and gain their early identity in the embryonic brains. However, the mechanism by which the brain milieu confers microglial maturation signature remains elusive. Here, we demonstrate that the baxcq55 zebrafish and Baxtm1Sjk mouse embryos exhibit similarly defective early microglial maturation. BAX, a typical pro-apoptotic factor, is highly enriched in neuronal cells and regulates microglial maturation through both pro-apoptotic and non-apoptotic mechanisms. BAX regulates dlb via the CaMKII-CREB axis calcium-dependently in living neurons while ensuring the efficient Notch activation in the immigrated pre-microglia by apoptotic neurons. Notch signaling is conserved in supporting embryonic microglia maturation. Compromised microglial development occurred in the Cx3cr1Cre/+Rbpjfl/fl embryonic mice; however, microglia acquire their appropriate signature when incubated with DLL3 in vitro. Thus, our findings elucidate a BAX-CaMKII-CREB-Notch network triggered by the neuronal milieu in microglial development, which may provide innovative insights for targeting microglia in neuronal disorder treatment. The mechanisms by which the brain milieu confers microglial development are not clear. Here, the authors show that the BAX-CaMKII-CREB-Notch signaling axis triggered by the neuronal milieu plays a role in early microglia maturation.
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