The embryonic zebrafish brain is seeded by a lymphatic-dependent population of mrc1+ microglia precursors

Microglia are the resident macrophages of the CNS that serve critical roles in brain construction. Although human brains contain microglia by 4 weeks gestation, an understanding of the earliest microglia that seed the brain during its development remains unresolved. Using time-lapse imaging in zebrafish, we discovered a mrc1a + microglia precursor population that seeds the brain before traditionally described microglia. These early microglia precursors are dependent on lymphatic vasculature that surrounds the brain and are independent of pu1 + yolk sac-derived microglia. Single-cell RNA-sequencing datasets reveal Mrc1 + microglia in the embryonic brains of mice and humans. We then show in zebrafish that these early mrc1a + microglia precursors preferentially expand during pathophysiological states in development. Taken together, our results identify a critical role of lymphatics in the microglia precursors that seed the early embryonic brain. Green and O’Dea et al. identify that the embryonic zebrafish brain is colonized by a population of early-colonizing microglia that are dependent on lymphatic vessels, placing lymphatic cells at the epicenter of microglia development.