Microglia development follows a stepwise program to regulate brain homeostasis

In the citing paper

“Gene expression studies have shown that microglial cells have distinct profiles during the embryonic, early post-natal, and adult stages (26).”

In the citing paper

“MAFB is known to play a key role in the final stages of microglial development from yolk sac progenitors, supporting the acquisition and maintenance of microglial identity (19).”

In the citing paper

“Additionally, it promotes the final stages of microglial development from yolk sac progenitors, facilitating the acquisition and maintenance of microglia identity (19).”

In the citing paper

“Integration of these findings with recent studies of yolk sac and embryonic microglia (56, 63) suggests a model by which intersecting developmentally determined and environment-dependent transcriptional networks establish microglia identity and function (Fig. 6E).”

In the citing paper

“Mcm5, an established regulator of microglial cell cycle that is strongly expressed during embryonic and early postnatal microglial development”

In the citing paper

“To minimize the reported effect of brain region on microglial gene expression 6,23,24 , only cortical microglia were included in our comparisons.”

In the citing paper

“An extensive overlap was observed between human and these three independent mouse microglial gene expression data sets ( Fig. 2c ). The median ∆ percentiles were 14.3, 20.4 and 9.3 for our own expression data set, that of Grabert et al. 23 and that of Matcovich-Natan et al. 24 , respectively.”

In the citing paper

“Microglia from adult GF mice also display differential expression of genes associated with microglial maturation, including down-regulation of genes that regulate cell activation and immune system defense pathways, such as Mapk8, IL-1α, Ly86, Jak3, and Stat1, all of which are normally highly expressed in adult microglia (Fig. 1; Erny et al., 2015; Matcovitch-Natan et al., 2016).”

In the citing paper

“However, the differences in the microglial transcriptome seen in offspring from MIA versus healthy dams decline as mice reach adulthood.”

In the citing paper

“Microglia from young MIA offspring show increased expression of inflammation-related genes typically associated with an adult microglial phenotype and down-regulation of genes expressed during earlier developmental stages (e.g., Pu.1 and Irf8), suggesting that maternal inflammation disrupts the timeline of normal microglial maturation (Matcovitch-Natan et al., 2016).”

In the citing paper

“While commensal symbiotic bacteria are critical for proper microglial maturation, induction of infection in pregnant dams can have disruptive effects on the progression of microglial development in offspring (Pratt et al., 2013; Matcovitch-Natan et al., 2016; Mattei et al., 2017).”

In the citing paper

“We found that microglial diversity is highest during early development, when microglia are still differentiating (Matcovitch-Natan et al., 2016).”

In the citing paper

“These signatures - cell cycle, phagocytosis, and surveillance - correspond with only three of the nine states presented here (Matcovitch-Natan et al., 2016).”

In the citing paper

“our new cluster definitions highlight the greater degree of developmental complexity that were covered up by dominating signatures in bulk sequencing experiments.”

In the citing paper

“This study uses single-cell RNA-sequencing and bioinformatics to describe microglial transcriptome profiles and temporal stages of development in early, pre-adult microglia, which are regulated by distinct regulatory circuits.”

In the citing paper

“GF mice display marked defects in microglia structure and function and hence feature impaired CNS innate immune responses.240,241”

In the citing paper

“our study detected about 3 times as many genes per cell, and produced higher detection rates for over 80% of genes”

In the citing paper

“which consists of three distinct temporal stages: early microglia spanning until embryonic day 14, premicroglia from embryonic day 14 to a few weeks after birth, and adult microglia from a few weeks after birth onward [13].”

In the citing paper

“In mice, microglia undergo a step-wise program of maturation that is synchronized with the developmental phases of the brain [13, 14]”

In the citing paper

“ATAC-seq of isolated microglia across different developmental stages showed that accessibility of promoter regions by transcriptional complexes was largely conserved over time [13, 34].”

In the citing paper

“Hippocampal microglial cells from polyI:C offspring mice showed dysregulation of genes associated with inflammatory response, cell migration and phagocytosis [13, 59, 60].”

In the citing paper

“Maternal immune activation (MIA) by administration of polyinosinic:polycytidylic acid (polyI:C), which is a synthetic analog of double-stranded RNA used to simulate viral infections via interaction with TLRs, can disrupt pre-microglial development in offspring, leading to a more advanced developmental stage.”

In the citing paper

“showing dramatic differences in microglial gene expression between early postnatal periods (P3–9) and adulthood (2 months) (Matcovitch-Natan et al., 2016).”

In the citing paper

“The cerebellar microglia phenotype is reminiscent of microglia during early brain development9,10 as well as microglia associated with neurodegenerative disease11–13.”

In the citing paper

“Furthermore, cbMg show an increase in the expression of genes characteristic of immature microglia9,10, as well as genes that are expressed in neurodegenerative disease-associated microglia (such as primed microglia, MGnD, and DAMs)11–13 (Supplementary Fig. 5c,d, Supplementary Table 4).”

In the citing paper

“We found that the cbMg-specific clearance gene expression pattern significantly overlaps with the signature of microglia associated with neurodegeneration11–13 and early brain development9,10, two stages of life characterized by enhanced neuronal attrition and heightened microglia clearance activity.”

In the citing paper

“This is another key characteristic feature of early microglia progenitors9,10 as well as microglia exposed to dying neurons during different diseases11–13.”

In the citing paper

“iMGLs not cultured with neurons differentially expressed early microglia genes including FFAR2”

In the citing paper

“Another study with germ-free mice found functional defects in microglia and as a result observed heightened levels of proinflammatory cytokines IL-1B, IL-6, and TNF-alpha [39], indicating an impairment in immune function.”