Brain milieu induces early microglial maturation through the BAX-Notch axis

Fangying Zhao, Jiangyong He, Jun Tang, Nianfei Cui, Yanyan Shi, Zhifan Li, Shengnan Liu, Yazhou Wang, Ming Ma, Congjian Zhao, Lingfei Luo () and Li Li ()
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Fangying Zhao: Southwest University
Jiangyong He: Southwest University
Jun Tang: Southwest University
Nianfei Cui: Southwest University
Yanyan Shi: Southwest University
Zhifan Li: Southwest University
Shengnan Liu: Southwest University
Yazhou Wang: Fourth Military Medical University
Ming Ma: Southwest University
Congjian Zhao: Chongqing University of Posts and Telecommunications
Lingfei Luo: Southwest University
Li Li: Southwest University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33836-2

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