Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals.

Microglia are brain-resident macrophages playing pivotal roles in central nervous system (CNS) development and homeostasis. Yet, the cellular and molecular basis governing microglia maintenance remains largely unknown. Here, by utilizing a visible conditional knockout allele of gene (the master regulator for microglia/macrophage lineage development) to generate mosaic microglia populations in adult zebrafish, we show that while -deficient microglia are immediately viable, they are less competitive, and chronically eliminated through Tp53-mediated cell competition. Interestingly, when conditionally inactivating Pu.1 in adult (the orthologue of mouse ) null mutants, microglia are rapidly depleted via apoptosis, suggesting that Pu.1 and Spi-b regulate microglia maintenance in a dosage-dependent manner. The dosage-dependent regulation of microglia maintenance by PU.1/SPI1 is evolutionarily conserved in mice, as shown by conditionally inactivating single and both alleles in microglia, respectively. Collectively, our study reveals the conserved cellular and molecular mechanisms controlling microglia turnover and maintenance in teleosts and mammals.