Abstract:Microglia, the brain's resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using a prolonged colony-stimulating factor 1 receptor inhibitor (CSF1Ri) approach, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from the subventricular zone and associated white matter areas. Following CSF1Ri, these amoeboid cells migrate radially and tangential… Show more
“…Following unilateral transplantation, we observed partial microglial repopulation emanating from the injection site and the appearance of ''wavefronts'' of proliferative Ki67 + microglia adjacent to unoccupied regions of the brain (Figures 3H-3N). These wavefronts appear to be highly similar to those recently described during microglial repopulation following complete pharmacological depletion (Hohsfield et al, 2021). Thus, WT microglia appear capable of repopulating the entire brain of FIRE mice within 3 months.…”
Section: Ad Mice That Genetically Lack Microglia Exhibit Premature Le...supporting
“…Following unilateral transplantation, we observed partial microglial repopulation emanating from the injection site and the appearance of ''wavefronts'' of proliferative Ki67 + microglia adjacent to unoccupied regions of the brain (Figures 3H-3N). These wavefronts appear to be highly similar to those recently described during microglial repopulation following complete pharmacological depletion (Hohsfield et al, 2021). Thus, WT microglia appear capable of repopulating the entire brain of FIRE mice within 3 months.…”
Section: Ad Mice That Genetically Lack Microglia Exhibit Premature Le...supporting
“…Here, we identify specific remodeling states of microglia that persist following CSF1R inhibition showing reduced homeostatic gene expression. Other groups recently found small populations of CSF1R-independent or repopulating microglia in the brain, and we note similar patterns of gene expression, with reduced homeostatic genes such as Tmem119 and P2ry12 , and increased expression of genes such as Lyz2 ( Zhan et al, 2020 ; Hohsfield et al, 2021 ). In these microglia repopulation studies, it was proposed that more immature microglia survive CSF1R inhibition, but microglia maturation may not be a key factor in the context of development since we previously found greater dependence of retinal microglia on CSF1R at embryonic stages ( Anderson et al, 2019b ) than in postnatal retina ( Anderson et al, 2019a ).…”
Microglia serve critical remodeling roles that shape the developing nervous system, responding to the changing neural environment with phagocytosis or soluble factor secretion. Recent single-cell sequencing (scRNAseq) studies have revealed the context-dependent diversity in microglial properties and gene expression, but the cues promoting this diversity are not well defined. Here, we ask how interactions with apoptotic neurons shape microglial state, including lysosomal and lipid metabolism gene expression and dependence on Colony-stimulating factor 1 receptor (CSF1R) for survival. Using early postnatal mouse retina, a CNS region undergoing significant developmental remodeling, we performed scRNAseq on microglia from mice that are wild-type, lack neuronal apoptosis (Bax KO), or are treated with CSF1R inhibitor (PLX3397). We find that interactions with apoptotic neurons drive multiple microglial remodeling states, subsets of which are resistant to CSF1R inhibition. We find that TAM receptor Mer and complement receptor 3 are required for clearance of apoptotic neurons, but that Mer does not drive expression of remodeling genes. We show TAM receptor Axl is negligible for phagocytosis or remodeling gene expression but is consequential for microglial survival in the absence of CSF1R signaling. Thus, interactions with apoptotic neurons shift microglia toward distinct remodeling states and through Axl, alter microglial dependence on survival pathway, CSF1R.
“…Along with the hippocampus, the SVZ is a well-known niche for adult neurogenesis [ 140 , 141 , 142 ]. Due to its specific function in the brain, recent studies showed that a particular subpopulation of microglia might be involved in SVZ-specific neurogenesis [ 53 , 143 , 144 ]. One study demonstrated that microglia with a discrete morphology, such as having an amoeboid-like form and shorter branches, mediate SVZ neurogenesis [ 143 ].…”
Section: Intra- and Inter-regional Heterogeneity Of Astrocytes And Mi...mentioning
Although different regions of the brain are dedicated to specific functions, the intra- and inter-regional heterogeneity of astrocytes and microglia in these regions has not yet been fully understood. Recently, an advancement in various technologies, such as single-cell RNA sequencing, has allowed for the discovery of astrocytes and microglia with distinct molecular fingerprints and varying functions in the brain. In addition, the regional heterogeneity of astrocytes and microglia exhibits different functions in several situations, such as aging and neurodegenerative diseases. Therefore, investigating the region-specific astrocytes and microglia is important in understanding the overall function of the brain. In this review, we summarize up-to-date research on various intra- and inter-regional heterogeneities of astrocytes and microglia, and provide information on how they can be applied to aging and neurodegenerative diseases.
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