Microglial colonisation of the developing brain is facilitated by clonal expansion of highly proliferative progenitors and follows an allometric scaling

Abstract

Microglia are the resident immune cells of the brain and arise from yolk sac-derived macrophages during early embryogenesis. On entering the brain, microglia undergo in situ proliferation and eventually colonise the entire brain by the second and third postnatal weeks in mice. However, the intricate dynamics of their developmental expansion remain unclear. Here, we examine and characterise the proliferative dynamics of microglia during embryonic and postnatal development. Using complementary fate-mapping techniques, we demonstrate that the developmental colonisation of the brain by microglia is facilitated by clonal expansion of highly proliferative microglial progenitors that occupy spatial niches throughout the brain. We also find that the distribution of microglia switches from a clustered to a random pattern between embryonic and late postnatal development. Moreover, the developmental increase in microglia follows the proportional growth of the brain in an allometric manner with the density of microglia eventually stabilising when the mosaic distribution has been established. Overall, our findings offer insight into how the competition for space acts as a driving force for microglial colonisation by clonal expansion during development.

epDevAtlas: Mapping GABAergic cells and microglia in postnatal mouse brains

“…5a, c-f ). This mosaic-like distribution achieved by the end of the second postnatal week is then maintained into adulthood, although regional heterogeneity exists 33,51 .…”

“…5a, c-f). This mosaic-like distribution achieved by the end of the second postnatal week is then maintained into adulthood, although regional heterogeneity exists 33,51 . In telencephalic regions, encompassing both cortical and striatal areas, microglia displayed the most rapid expansion in density, with an approximately 200% increase from P4 to P14 (Fig.…”

Plaque vicinity as a hotspot of microglial turnover in a mouse model of Alzheimer's disease

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“…To overcome these methodological issues, we developed an approach for the visualization and longitudinal in vivo monitoring of microglia with the help of microRNA‐9 (miR9)‐regulated lentiviral vectors (Akerblom et al, 2013; Barry‐Carroll et al, 2023; Brawek et al, 2017). In these experimental settings, random expression of three different fluorescent proteins (mCherry, mVenus, and mTurquoise) allows labeling of microglia with a variety of different colors and thus unambiguous identification of individual cells.…”

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“…Microglia play a pivotal role in brain development, maintenance of brain health, and regulation of neural activity 27 . However, there are currently limited AAVs available for studying and understanding microglia, possibly due to immunogenicity or the insufficient affinity of existing AAVs for microglia.…”