Homeostatic, phagocytic, NRF2/Hmox1, Apoc1 and chemokine microglia transcriptional programmes in naive mouse cerebral cortex from embryo to adulthood

Abstract

Microglia, the resident immune cells of the central nervous system, undergo dynamic transcriptional remodeling across embryonic and postnatal development. However, the precise transcriptional programmes governing these transitions, and the role of oxidative stress pathways such as NRF2/Hmox1 in shaping microglial maturation, remain incompletely understood. Here, we characterized the transcriptional landscape of mouse microglial development using pseudobulk RNA-sequencing data, spanning five developmental stages, from embryonic day 17 to postnatal day 60. We identified four distinct transcriptional programmes (homeostatic, phagocytic, NRF2/Hmox1 oxidative stress-responsive, and Apoc1-associated) whose relative activities shift coordinately across development. Early developmental microglia were dominated by phagocytic and NRF2/Hmox1-associated gene expression, while mature microglia progressively acquired a homeostatic transcriptional identity marked by Tmem119 and P2ry12. Pseudotime trajectory analysis confirmed a continuous developmental axis along which the phagocytic programme declined, homeostatic programme increased, and NRF2/Hmox1 activity peaked at intermediate stages. Differential expression analysis distinguished Tmem119+ homeostatic microglia from Tmem119- populations, and early developmental from mature microglial states. Additionally, chemokine receptor expression, including Cxcr4 at early timepoints, suggested a role for chemokine signaling in microglial migration and tissue integration during brain development. Collectively, these findings support a model in which microglial maturation proceeds along a transitional regulatory role during brain development.