Microglial colonization of the developing mouse brain is controlled by both microglial and neural CSF-1

Microglia are brain-resident macrophages critical for cerebral development, function, and homeostasis. During development, yolk sac-derived microglial progenitor cells colonize and populate the brain following a well-defined spatiotemporal pattern. However, the mechanisms controlling microglial colonization and proliferation remain largely unknown. Here, we describe two broad waves of microglial proliferation in the developing mouse forebrain. Microglia accumulate in transient hotspots, in a proliferative axon tract-associated microglia (ATM)-like state. Prenatal and early postnatal patterns of microglial colonization do not rely on neuronal activity. Instead, using conditional inactivation of the microglial regulator colony-stimulating factor 1 (Csf1) gene, we reveal that the distribution and proliferation of embryonic cortical microglia critically rely on neural CSF-1, mainly produced by cortical progenitor cells but also by post-mitotic neurons, with the action of CSF-1 being local, dose-dependent, and transient. In addition, intrinsic CSF-1 expressed by ATM microglia contributes to their sustained proliferation in developmental hotspots. Our study reveals that microglia rely on distinct, local, and cell-type-specific sources of CSF-1 for their developmental distribution, which has major implications for understanding how microglia colonize the brain in health and disease.