MICROGLIA – EXTRACELLULAR MATRIX INTERACTIONS IN MAINTAINING TISSUE INTEGRITY DURING BRAIN DEVELOPMENT

Microglia (MG), the brain-resident macrophages, play major roles in health and disease through a diversity of cellular and transcriptional states. Yet, we still have limited understanding of how these states contribute to specific microglial functions. We recently uncovered a new role for MG in the embryonic brain, associated with a MG state resembling postnatal axon tract-associated microglia (ATM). Embryonic ATM accumulate at fetal cortical boundaries that are sites of high morphogenetic tensions, preventing the progression of microcavities into large cavitary lesions and contributing to their repair. ATM show highly phagocytic profiles and engulf fibronectin (FN), a major component of the fetal extracellular matrix (ECM). Since ECM phagocytosis and remodeling by macrophages are important for tissue repair and wound healing, this raises the possibility that reciprocal interactions between ATM and the ECM contribute to the maintenance of fetal brain tissue integrity. Here, we employ pharmacological and genetic mouse models of microglia depletion and alteration to investigate MG-FN interactions at cavitary lesion sites. Combining ex vivo and in vivo analyses, we show that ATM engage in close interactions with FN and that lesion formation and repair are associated with FN deposition and clearance, respectively. Altogether, these findings suggest that ECM remodeling is part of the key developmental neuroprotective functions of microglia and provides insights into possible prevention of long-term deleterious effects of early brain lesions.