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 <i>pu.1/spi1b</i> gene (the master regulator for microglia/macrophage lineage development) to generate mosaic microglia populations in adult zebrafish, we show that while <i>pu.1</i>-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 <i>spi-b</i> (the orthologue of mouse <i>Spi-b</i>) 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 <i>Spi1</i> alleles in microglia, respectively. Collectively, our study reveals the conserved cellular and molecular mechanisms controlling microglia turnover and maintenance in teleosts and mammals.