Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen, China
Biomedical Research Institute, Shenzhen Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen, China; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen, China
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 pu.1/spi1b gene (the master regulator for microglia/macrophage lineage development) to generate mosaic microglia populations in adult zebrafish, we show that while pu.1-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 spi-b (the orthologue of mouse Spi-b) 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 Spi1 alleles in microglia, respectively. Collectively, our study reveals the conserved cellular and molecular mechanisms controlling microglia turnover and maintenance in teleosts and mammals.
