Microglia development follows a stepwise program to regulate brain homeostasis

Abstract

Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.

Transcriptional control of microglia phenotypes in health and disease

“…Substantial subsets of genes associated with risk alleles for neurodegenerative or behavioral diseases exhibited environment-dependent expression (37). Genes that were downregulated in vitro were highly correlated with genes that are upregulated in primitive macrophages following their migration into the fetal brain (28,37). These changes in gene expression are associated with downregulation of numerous putative microglia LDTFs, such as Sall1 and corresponding alterations in enhancer landscapes.…”

“…In the yolk sac EMPs differentiate into premacrophages (pMacs) that express a core macrophage program that includes the receptors CX3CR1 and CSF1R, as well as the TFs Maf, Batf3, Pparg, Irf8, and zinc finger E-box binding homeobox-2 (Zeb2) (27), a program that persists when these precursors infiltrate various organs to establish resident macrophage populations. Microglia development has been proposed to progress in three developmental stages (28): early microglia (until E14), premicroglia (from E14 to the first weeks after birth), and adult microglia (from a few weeks after birth onward). Early microglia, like EMPs, express genes associated with cell cycle signaling pathways and the TF E2f6 and DNA methyltransferase-1 (Dnmt1), which may help them populate the brain.…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Microglia engage in constructive pruning to maintain synaptic and functional specialization during critical developmental phases and in neurogenesis (Matcovitch-Natan et al, 2016;Schafer and Stevens, 2015). In contrast, toxic pruning by microglia results from excessive immune activation and aggressive neural signaling (eg, during prenatal infections and severe stress) and appears to move the trajectory toward synaptic destruction or aberrant synaptic construction (Brites and Fernandes, 2015).…”

Microglia in prion diseases

“…Microglia are resident myeloid cells of the CNS that originate from c-Kit + erythromyeloid precursors in the yolk sac and migrate to the developing neural tube for maturation, following a stepwise developmental program (7)(8)(9)(10)(11). Microglia play crucial roles in early development of the brain as well as the maintenance of brain homeostasis throughout life.…”