Border-associated macrophages transventricularly infiltrate the early embryonic cerebral wall to differentiate into microglia

Abstract

The relationships between microglia and macrophages, especially their lineage segregation outside the yolk sac, have been recently explored, providing a model in which a conversion from macrophages seeds microglia during brain development. However, spatiotemporal evidence to support such microglial seeding and to explain how it occurs has not been obtained. By cell tracking via slice culture, intravital imaging, and Flash tag-mediated labeling, we found that a group of intraventricular macrophages belonging to border-associated macrophages (BAMs), which were abundantly observed along the inner surface of the mouse cerebral wall at embryonic day 12, frequently entered the brain wall. Immunohistochemistry of the tracked cells showed that postinfiltrative BAMs acquired microglial properties while losing a macrophage phenotype. We also found that the intraventricular BAMs were supplied transepithelially from the roof plate. Thus, this study demonstrates that the ″roof plate→ventricle→cerebral wall″ route is an essential path for microglial colonization into the embryonic mouse brain.

Multifaceted microglia during brain development: Models and tools

“…While some experiments are performed on brain slices, inducing tissue damage and possibly altering microglial behavior, most studies use cranial windows or skull thinning that allows microglial observation in their homeostatic environment. For pups, adapted approaches are being developed taking advantage of the thinness of the embryonic skull to perform ex utero live-imaging of microglia and macrophages in the brain of intact embryos (Hattori et al, 2020(Hattori et al, , 2022Munz et al, 2022), that will probably be critical to better characterize key aspects of microglia development such as their entry in the brain parenchyma (Stremmel et al, 2018). As a self-renewing population arising from a restricted pool of pioneer cells, the questions of microglial expansion during development, their migration and turnover were raised-and still retain some mystery.…”