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

Area of Science:

• Neuroscience
• Developmental Biology
• Immunology

Background:

• Microglia originate from primitive myeloid cells and establish their identity in embryonic brains.
• The precise mechanisms by which the brain microenvironment influences microglial maturation are not fully understood.

Purpose of the Study:

• To elucidate the role of BAX in embryonic microglial maturation.
• To identify the signaling pathways involved in neuronal regulation of microglia development.

Main Methods:

• Utilized bax mutant zebrafish (bax^cq55) and mouse (Bax^tm1Sjk) embryos to assess microglial maturation.
• Investigated the BAX-CaMKII-CREB axis and Notch signaling in neuronal regulation of microglia.
• Examined microglial development in Cx3cr1^Cre/+Rbpj^fl/fl mice and in vitro cultures with DLL3.

Main Results:

• Defective early microglial maturation was observed in bax mutant embryos.
• BAX regulates microglial maturation through both pro-apoptotic and non-apoptotic neuronal mechanisms.
• A BAX-CaMKII-CREB-Notch signaling network, triggered by neuronal apoptosis and calcium signaling, was identified as critical for microglia maturation.

Conclusions:

• Neuronal BAX and its downstream signaling pathways are essential for embryonic microglia development.
• The findings highlight a novel neuronal-microglial communication axis crucial for brain development.
• This research offers potential therapeutic strategies for neuronal disorders by targeting microglial development.