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

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.

Human stem cell transplantation models of Alzheimer’s disease

“…The brain harbors immense complexity and heterogeneity, and although in vitro culture platforms are instrumental for disease modeling, they are at this point still unable to encompass the diverse cellular interactions of the brain. As a few examples, the neuronal milieu promotes the maturation of microglia ( Zhao et al, 2022 ), microglia modulate neurogenesis ( Shigemoto-Mogami et al, 2014 ), and capillary-associated microglia regulate the structure and function of blood vessels within the brain ( Bisht et al, 2021 ). Exposure of human cells to this highly organized microenvironment with its complex cell–cell interactions and various soluble factors provides important advantages for disease modeling, as it promotes increased cellular maturation and integration into functional circulatory systems, which in turn helps to better characterize phenotypic and functional differences between healthy control and patient cells.…”

Central Causation of Autism/ASDs via Excessive [Ca2+]i Impacting Six Mechanisms Controlling Synaptogenesis during the Perinatal Period: The Role of Electromagnetic Fields and Chemicals and the NO/ONOO(-) Cycle, as Well as Specific Mutations

“…Sudarov et al [57] showed that CamKII controls both synaptogenesis and autism-like behavior in mice. CamKII also regulates the activity of each of the six mechanisms proposed here to have important roles in both synaptogenesis and ASD causation: neuronal migration [58,59], dendritic outgrowth [58,60,61], synapse formation [58,[62][63][64], synapse maturation [64][65][66][67], synaptic pruning [58,64,66,67], and MeCP2 activity [68,69]. While the studies cited in this paragraph implicate CamKII in producing aberrant synaptogenesis in autism/ASDs, they do not imply that CamKIIdependent protein phosphorylation is the sole or predominant [Ca 2+ ]i-dependent causal mechanism of either synaptogenesis or ASD causation.…”

“…Valproic acid has been shown to cause hepatotoxicity, especially in very young individuals [172]. Therefore, it may act to cause autism [67,[173][174][175] via hepatic encephalopathy, where liver toxicity leads to ammonia accumulation and excess ammonia acts to increase glutamatergic activity, including excessive NMDA-R activity. Ammonia does this via inhibition of the glutamate transporter, such that glutamate neurotransmission in the brain is excessive following valproic acid exposure.…”