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

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. 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.