Microglia maintain structural integrity during fetal brain morphogenesis.

Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.

Multifaceted microglia during brain development: Models and tools.

Microglia, the brain resident macrophages, are multifaceted glial cells that belong to the central nervous and immune systems. As part of the immune system, they mediate innate immune responses, regulate brain homeostasis and protect the brain in response to inflammation or injury. At the same time, they can perform a wide array of cellular functions that relate to the normal functioning of the brain. Importantly, microglia are key actors of brain development. Indeed, these early brain invaders originate outside of the central nervous system from yolk sac myeloid progenitors, and migrate into the neural folds during early embryogenesis. Before the generation of oligodendrocytes and astrocytes, microglia thus occupy a unique position, constituting the main glial population during early development and participating in a wide array of embryonic and postnatal processes. During this developmental time window, microglia display remarkable features, being highly heterogeneous in time, space, morphology and transcriptional states. Although tremendous progress has been made in our understanding of their ontogeny and roles, there are several limitations for the investigation of specific microglial functions as well as their heterogeneity during development. This review summarizes the current murine tools and models used in the field to study the development of these peculiar cells. In particular, we focus on the methodologies used to label and deplete microglia, monitor their behavior through live-imaging and also discuss the progress currently being made by the community to unravel microglial functions in brain development and disorders.

Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration.

Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.