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

Abstract Microglia are brain-resident macrophages that play pivotal roles in CNS development and homeostasis. Yet, the cellular and molecular basis governing microglia maintenance remain largely unknown. By using a visible conditional knockout strategy to generate mosaic zebrafish, we show that microglia deficient for Pu.1/Spi1b, the master regulator for microglia development, are less competitive and chronically eliminated in a Tp53-dependent manner. Interestingly, when both Pu.1 and Spi-b (the paralogue of Pu.1 in zebrafish, also called Spi1a) are defective, microglia are rapidly depleted via apoptosis, suggesting that Pu.1 and Spi-b regulate the maintenance of microglia in a dosage-dependent manner. More importantly, the dosage dependent regulation of microglia maintenance by Pu.1/Spi1 is also evolutionarily conserved in mouse, as revealed by conditional knockout of Pu.1 by 1 or 2 alleles in microglia respectively. Collectively, our data pinpoints the conserved cellular and molecular mechanisms controlling microglia turnover and maintenance in teleost and mammals.