Spatiotemporal dynamics of the CD11c+ microglial population in the mouse brain and spinal cord from developmental to adult stages

Abstract

CD11c-positive (CD11c+) microglia have attracted considerable attention because of their potential implications in central nervous system (CNS) development, homeostasis, and disease. However, the spatiotemporal dynamics of the proportion of CD11c+ microglia in individual CNS regions are poorly understood. Here, we investigated the proportion of CD11c+ microglia in six CNS regions (forebrain, olfactory bulb, diencephalon/midbrain, cerebellum, pons/medulla, and spinal cord) from the developmental to adult stages by flow cytometry and immunohistochemical analyses using a CD11c reporter transgenic mouse line, Itgax-Venus. We found that the proportion of CD11c+ microglia in total microglia varied between CNS regions during postnatal development. Specifically, the proportion was high in the olfactory bulb and cerebellum at postnatal day P(4) and P7, respectively, and approximately half of the total microglia were CD11c+. The proportion declined sharply in all regions to P14, and the low percentage persisted over P56. In the spinal cord, the proportion of CD11c+ microglia was also high at P4 and declined to P14, but increased again at P21 and thereafter. Interestingly, the distribution pattern of CD11c+ microglia in the spinal cord markedly changed from gray matter at P4 to white matter at P21. Collectively, our findings reveal the differences in the spatiotemporal dynamics of the proportion of CD11c+ microglia among CNS regions from early development to adult stages in normal mice. These findings improve our understanding of the nature of microglial heterogeneity and its dynamics in the CNS.

CD11c-expressing microglia are transient, driven by interactions with apoptotic cells

“…In adult retina, CD11c+ microglia density is low, but following optic nerve crush, CD11c+ myeloid cells increase in number and play a prominent role in the clearance of retinal ganglion cell and axonal debris (34), with evidence that some CD11c+ cells are recruited into the retina from the myelinated optic nerve (35). The transcriptional profile of CD11c+ microglia is overlapping with the transcriptome signatures described for proliferative associate microglia (PAM) and axon tract associated microglia (ATM) in developing brain, and related to gene signatures associated with aging and neurodegenerative disease (8, 11, 14, 36, 37), raising the possibility of related cues driving these microglial states.…”

“…Using a genetic lineage-tracing strategy, we find evidence that CD11c+ microglia reintegrate into the homeostatic pool of microglia within the retina, since from P5 to P30 the loss of CD11c-active microglia was proportional to the increase in CD11c-lineage microglia while the CD11c-negative microglia remain stable. To date, there have been conflicting data on whether CD11c+ microglia represent a stable subset that emerges in development and is maintained through adulthood (8, 9, 11), or a state achieved through recognition of molecular cue(s) (5, 6, 14). Altogether, our data suggest CD11c expression is transiently expressed in response to exposure to apoptotic neurons, and microglia shift back into a CD11c-state rather than being maintained as a stable subset.…”

“…By single-cell RNA sequencing, we found heterogeneity in CD11c+ microglia, but all CD11c+ microglia expressed genes associated with phagocytosis and lysosomal function (6). In the developing CNS, CD11c+ microglia predominantly reside in white matter tracts (8-10) and have dynamic regional density changes over development in brain and spinal cord (11). CD11c+ microglia are increased in diverse disease states.…”