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

• Published in: Nature communications Vol. 13; no. 1; p. 6117
• Main Authors: Zhao, Fangying, He, Jiangyong, Tang, Jun, Cui, Nianfei, Shi, Yanyan, Li, Zhifan, Liu, Shengnan, Wang, Yazhou, Ma, Ming, Zhao, Congjian, Luo, Lingfei, Li, Li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.10.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 14/32; 14/34; 38/1; 38/23; 38/39; 38/47; 38/77; 38/88; 45/41; 631/136/142; 631/208/135; 631/250/2502/248; 631/378/2596/1953; 631/80/86/1999; 64/116; 64/60; 82/1; 96/44; Animals; Apoptosis; bcl-2-Associated X Protein - genetics; Brain; Ca2+/calmodulin-dependent protein kinase II; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cyclic AMP response element-binding protein; Embryogenesis; Humanities and Social Sciences; Maturation; Mice; Microglia; multidisciplinary; Myeloid cells; Neurons; Science; Science (multidisciplinary); Signaling; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33836-2

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 bax cq55 zebrafish and Bax tm1Sjk 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 Cx3cr1 Cre/+ Rbpj fl/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.